A Screening-Based Approach to Circumvent Tumor Microenvironment

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Journal of Biomolecular Screening 2014, Vol 19(1) 158–167 A Screening-Based Approach to © 2013 Society for Laboratory Automation and Screening DOI: 10.1177/1087057113501081 Circumvent Tumor Microenvironment- jbx.sagepub.com Driven Intrinsic Resistance to BCR-ABL+ Inhibitors in Ph+ Acute Lymphoblastic Leukemia

Harpreet Singh1,2, Anang A. Shelat3, Amandeep Singh4, Nidal Boulos1, Richard T. Williams1,2*, and R. Kiplin Guy2,3

Abstract Signaling by the BCR-ABL fusion kinase drives Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their clinical activity in many patients with CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib, and nilotinib provide only transient leukemia reduction in patients with Ph+ ALL. While host-derived growth factors in the leukemia microenvironment have been invoked to explain this drug resistance, their relative contribution remains uncertain. Using genetically defined murine Ph+ ALL cells, we identified interleukin 7 (IL-7) as the dominant host factor that attenuates response to BCR-ABL-KIs. To identify potential combination drugs that could overcome this IL-7–dependent BCR-ABL-KI–resistant phenotype, we screened a small-molecule library including Food and Drug Administration–approved drugs. Among the validated hits, the well-tolerated antimalarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and modest in vivo monotherapy activity against engineered murine BCR-ABL-KI–resistant Ph+ ALL. Strikingly, cotreatment with DHA and dasatinib in vivo strongly reduced primary leukemia burden and improved long-term survival in a murine model that faithfully captures the BCR-ABL-KI–resistant phenotype of human Ph+ ALL. This cotreatment protocol durably cured 90% of treated animals, suggesting that this cell- based screening approach efficiently identified drugs that could be rapidly moved to human clinical testing.

Keywords phenotypic drug discovery, cancer and cancer drugs, cell-based assays, kinases

Introduction 1Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA Targeted BCR-ABL inhibition with imatinib has improved 2 1 Integrated Program in Biomedical Sciences, University of Tennessee outcome for chronic myelogenous leukemia (CML). Health Science Center, Memphis, TN, USA However, the situation is starkly different for pediatric and 3Department of Chemical Biology and Therapeutics, St. Jude Children’s adult Philadelphia chromosome–positive acute lymphoblas- Research Hospital, Memphis, TN, USA 4 tic leukemia (Ph+ ALL).2 While continuous BCR-ABL Department of Medicine, Kings County Hospital Center, Brooklyn, NY, inhibition therapy—using imatinib, nilotinib, or dasatinib— USA *Current address: Puma Biotechnology, Inc., Los Angeles, CA potently kills Ph+ ALL cells in vitro, these drugs induce only transient remissions in patients with Ph+ ALL, ultimately Received Apr 10, 2013, and in revised form May 31, 2013. Accepted for allowing relapse and giving poor long-term outcomes. publication Jul 20, 2013. Although additional chemotherapy and hematopoietic stem Supplementary material for this article is available on the Journal of cell transplantation (HSCT) improve the remission rate in Biomolecular Screening Web site at http://jbx.sagepub.com/supplemental. Ph+ ALL patients, relapses remain common,3 with an 18- to 24-month survival rate of 64% and an even worse relapse- Corresponding Author: free survival rate.3 Differences in primary responses to BCR- R. Kiplin Guy, PhD, Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, ABL kinase inhibitors (BCR-ABL-KIs) in patients with Ph+ Memphis, TN 38105-3678, USA. ALL and CML remain poorly understood and cannot be Email: [email protected]

Downloaded from jbx.sagepub.com by guest on December 19, 2013 Singh et al. 159 attributed solely to mutations in the ABL kinase domain 95% viability at 24 h), PCR genotyping to confirm Arf –/– sta- (BCR-ABLMUTANTS).4 tus, mycoplasma testing (negative by Takara Bio Mycoplasma We previously developed a murine leukemia model of PCR assay [Clontech, Madison, WI]), sequence verification Ph+ ALL, using primary, polyclonal Arf –/– p185BCR-ABL of the BCR-ABL allele, and in vitro dasatinib potency luciferase-expressing (Luc+) leukemia-initiating pre–B confirmation. cells (LICs), which captures key genetic features of human The maximum DMSO concentration tolerated by LICs Ph+ ALL (i.e., BCR-ABL expression and CDKN2A dele- in culture was determined to be 0.2% (by volume) and was tion) and enables in vivo luminescent imaging to monitor maintained at ≤0.1% (by volume) in all subsequent work. response to therapy.5 Such BCR-ABLWT LICs retain pheno- LICs were plated in 384-well microplates at a cellular den- typic and signaling properties essential for suspended leu- sity of 5 × 104 per milliliter (1250 LICs per well in 25 µL kemic blasts to interact with the surrounding host BCM10) and confirmed to give exponential growth during environment6 not typically present in established leukemic the first 72 h (Suppl. Fig. S1). To select assay reagents, cell lines and remain responsive to cytokines implicated in three high-throughput screening (HTS) relevant cellular murine pre–B-cell development both in vitro and in vivo.6 assays were evaluated according to the manufacturer’s These polyclonal BCR-ABLWT LICs can very efficiently instructions (see Suppl. Fig. S3). The luminescent CTG initiate leukemias in syngeneic, immune-competent mice.6 (CellTiter-Glo; Promega, Madison, WI) assay, which moni- In “recipient” host mice engrafted with these LICs, residual tors cellular adenosine triphosphate (ATP) content, accu- BCR-ABLWT cells5 evade treatment with BCR-ABL inhibi- rately detected a low number of LICs, producing results tors, paralleling what is seen in human Ph+ ALL patients.4 comparable to those obtained by flow cytometry, and pro- BCR-ABL kinase domain (KD) mutations, including BCR- vided ease of use in HTS (no prolonged incubation step ABLT315I (resistant to imatinib, dasatinib, and nilotinib), required between reagent addition and assay readout). emerge only after long-term exposure to BCR-ABL-KIs.5,7 In When carried out after 72 h, the CTG assay had a 10,000- contrast to the in vivo setting, BCR-ABLWT murine and human fold dynamic range, had low signal variance (Z′ = 0.9 in cells are quite sensitive to BCR-ABL-KIs in vitro.8 This dis- semi-automated mode and Z′ = 0.8 in fully automated parity between in vitro and in vivo sensitivity implicates the mode), displayed minimal drift or edge effects, and had host microenvironment in attenuating the therapeutic response robust interplate and interday reproducibility. to BCR-ABL kinase inhibition. We previously reported that common γ chain receptor host cytokines modulate primary imatinib resistance,6 and other host-derived growth factors Forward Cytokine Phenotypic Screen 9–11 have been shown to attenuate BCR-ABL kinase inhibition. Lyophilized murine and human recombinant cytokines (R&D Currently, no consensus exists on the relative importance of Systems, Minneapolis, MN) were diluted with 1 mg/mL host cytokines or growth factors that attenuate the cellular bovine serum albumin (BSA) in sterile phosphate-buffered responses to BCR-ABL–targeted agents. saline (PBS) to a final concentration of 20 µg/mL and stored at We used a naive screening approach to identify interleukin 4 °C. Antileukemia drugs, BCR-ABL-KIs, and non–BCR- (IL)–7 as the most potent among candidate host growth factors ABL–specific KIs (LC labs; Sigma, St. Louis, MO) were solu- in inducing resistance to BCR-ABL-KIs in Ph+ ALL. bilized in DMSO to obtain 10-mM stock concentrations. Following on that study, we used a repurposing screen of exist- Subsequent serial titrations were prepared using DMSO in 0.5- ing drugs and clinical candidates to identify drugs that blocked WT mL vials or 384-well drug master plates and stored at –20 °C. proliferation of BCR-ABL LICs cultured with murine IL-7. To study the impact of murine cytokines on dasatinib This study identified both the majority of known antileukemic action, LIC stocks containing different concentrations of drugs and a few novel agents that could overcome cytokine- candidate cytokines were prepared in multichannel sterile dependent cell survival signaling. Testing of combinations of reservoirs and plated into 384-well plates. Drug delivery to these validated hits with dasatinib revealed that the antimalar- cell suspensions was accomplished with a V & P Scientific ial drug dihydroartemisinin (DHA) provides strong synergy (San Diego, CA) pin tool (Suppl. Table S1). For murine- with BCR-ABL-KIs against Ph+ ALL cells responding to the human comparisons, human SUP-B15 Ph+ ALL cells tumor microenvironment. When used in vivo, DHA-dasatinib (DSMZ cell culture collection, Liebniz, Germany) in combination therapy eradicates dasatinib-refractory leukemia McCoy’s media containing 20% fetal calf serum and peni- in vivo, providing near-complete long-term survival. cillin/streptomycin (Invitrogen, Carlsbad, CA) were plated at 12,500 cells in 25 µL/well in black clear-bottom 384-well Materials and Methods microplates. Drugs were transferred by pin transfer. After a Development of LIC-Based Screening Assay 72-h incubation at 37 °C, 20% (by volume) MTS assay reagent (CellTiter 96 Aqueous One Solution; Promega) was Before use in any in vitro assay, LICs had to pass the follow- added, and microplates were incubated for 75 min at 37 °C ing quality control parameters: test thawing (benchmark: and read colorimetrically at 490 nm.

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Figure 1. Interleukin 7 (IL-7) induces resistance to BCR-ABL kinase inhibitors (BCR-ABL-KIs) in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) without mutation of BCR-ABL. (a) Radar plot representing the effect of 15 hematopoietic cytokines on dasatinib potency (EC ) against Arf–/– BCR-ABLWT leukemia-initiating cells (LICs). The CTG assay measured LIC 50 populations after 72-h dasatinib exposures in the presence of increasing concentrations of indicated cytokines. Each spoke represents an individual cytokine; each line graph represents dasatinib proliferation inhibition EC50 (nM) at indicated titration of the parent cytokine (see Excel supplement). (b) Arf–/– BCR-ABLWT (triangles) and Arf–/– BCR-ABLT315I (circles) LICs were treated with drug or DMSO for 72 h in the absence (blue) or presence (red) of 1 ng/mL mIL-7, in triplicates. For each drug concentration, LIC growth measured by the CTG assay was normalized to DMSO-treated LICs and fit using nonlinear regression (±SD). (c) Viability of human Ph+ ALL SUPB15 cells, after 72-h drug treatment in the absence or presence of 25 ng/mL hIL-7, was measured by the MTS assay. Values were normalized to DMSO-treated cells. (d, e) Kaplan-Meier survival curves showing overall survival in IL-7+/+ and IL-7–/– Bl6 host mice receiving day 0 tail vein injection of (d) 2 × 102 Arf–/– BCR-ABLWT LICs (vehicle treated), with median survival of 20 days in IL-7+/+ (n = 4) versus 33 days in IL-7–/– mice (n = 4), p = 0.0069, or (e) 2 × 105 Arf–/– BCR-ABLWT LICs. Data are an average of two independent experiments in which vehicle or dasatinib therapy was initiated on day 7 or 9. Survivals of vehicle-treated IL-7+/+ and IL-7–/– mice were comparable. Dasatinib treatment caused a median survival of 33 days in IL-7+/+ (n = 12) versus 41 days in IL-7–/– (n = 11) mice, p = 0.0061.

High-Throughput Phenotypic Drug Screening signaling mechanisms was carried out at a fixed dose (10 µM). Active compounds were retested to establish potency The IL-7 concentration of 0.85 ng/mL was confirmed using a 10-step, 2-fold dilution scheme (see main text and (cytokine titration assays similar to Fig. 1a for dasatinib) to Suppl. Table S1). In addition to BCR-ABLWT and BCR- confer near-maximal and reproducible resistance against ABLT315I LICs, secondary drug screens were also performed nilotinib and imatinib in BCR-ABLWT LICs (Fig. 1b and against BCR-ABLF317L LICs, another clinically known dasat- Suppl. Table S1). Primary screening of a collection of 5600 inib-resistant ABL KD mutation, which gave identical results compounds (see supplementary information for details) to that for BCR-ABLT315I (not shown). Multiple control assay highly enriched for approved drugs, development candidates, plates were set up during all screening runs to allow for inter- and compounds of known cellular activity from a variety of plate and interday comparisons at 0, 24, 48, and 72 h.

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Supplementary Data Physiological Levels of IL-7 Confer an Supplementary data include (1) supplemental information Aggressive, Dasatinib-Resistant Phenotype (PDF), which contains materials and methods for genera- to Ph+ ALL In Vivo tion of LICs, cytokine screening, fluorescence-activated To confirm the physiological relevance of this finding, we cell sorting (FACS) assessment of viability and cell cycle studied the effect of IL-7 on leukemia progression and percentages, detailed description of chemical library dasatinib responsiveness in vivo. Implantation of IL-7+/+, screened, data processing, quality control and hit scoring but not IL-7–/–, host mice with relatively small numbers of criteria for high-throughput (HT) drug screens, cluster anal- BCR-ABLWT LICs (200, low-burden model) led to ysis using therapeutic drug classes, Supplemental Figures decreased survival (Fig. 1d), suggesting that murine Ph+ S1 to S11, Supplemental Table S1, and references, and (2) ALL progression accelerates in response to IL-7. Injecting an Excel supplement containing complete data sets for higher numbers of LICs (200,000) overcame this trend cytokine and HT drug screens. (200,000, high-burden model; Fig. 1e), suggesting the phenomenon is most important during expansion of the initial seeding leukemia cell population. Treatment of animals in Results the high-burden model revealed a significantly shortened survival benefit from dasatinib monotherapy of BCR- Determining Which Leukemia Microenvironment WT ABL –driven leukemias in IL-7–deficient hosts (Fig. 1e). Cytokines Induce Drug-Resistance against BCR- From a therapeutic perspective, these findings show that in ABL-KIs vivo responses to dasatinib therapy in Ph+ ALL are modu- –/– WT lated by IL-7, independent of BCR-ABL KD mutations. In the absence of drug treatment, both Arf p185 and WT Arf –/– p185T315I pre–B cells (referred to as BCR-ABLWT These studies also suggest that using the BCR-ABL LICs LICs12 and BCR-ABLT315I LICs, respectively) have iden- in the presence of IL-7 as a screening system could identify tical growth properties in vitro (Suppl. Fig. S1) and physiologically relevant pharmacological approaches to demonstrate similar, potent leukemia initiation capacity reversing this cytokine-dependent drug resistance. and aggressive progression in vivo (Suppl. Fig. S2). They retain both phenotypic and signaling characteristics High-Throughput Screens against Primary (IL- of leukemic blasts, suggesting that they are a ready model 7–Induced) and Acquired (BCR-ABL Mutation) for the effects of cytokines upon blasts. Fifteen leukemia BCR-ABL-KI Drug-Resistant Phenotypes microenvironment cytokines were evaluated for their ability to protect murine BCR-ABLWT LICs from dasat- We hypothesized that pharmacologic agents could be iden- inib in vitro. tified that would overcome IL-7–induced BCR-ABL-KI IL-7 provided the strongest protection against dasatinib resistance. A collection of 5600 compounds highly enriched (Fig. 1a). In addition, IL-3, thymic stromal lymphopoietin for approved drugs, development candidates, and com- (TSLP, IL-7–like cytokine), and IL-4 conferred some resis- pounds of known cellular activity from a variety of signal- tance but with greatly reduced potency. In contrast, trans- ing mechanisms, including all active ingredients from forming growth factor–β (TGF-β) enhanced dasatinib approved oncology and anti-infective drugs, was screened activity. In addition, IL-7 significantly attenuated the against BCR-ABLWT and BCR-ABLT315I LICs in the pres- potency of all Food and Drug Administration (FDA)– ence of IL-7 (0.85 ng/mL) at a fixed drug concentration (10 approved BCR-ABL-KIs against murine BCR-ABLWT µM). The quality of the screen and minimum significant LICs (Fig. 1b) and the human Ph+ ALL cell line SUP-B15 activity (>10% growth inhibition) were confirmed by (Fig. 1c). However, IL-7 did not affect the potency of tested receiver operating characteristic analysis and other statisti- non–BCR-ABL–targeted drugs (Suppl. Fig. S4). Thus, cal metrics (Suppl. Fig. S7–S10). In total, 627 compounds IL-7 drives a specific cellular response that provides resis- showed statistically significant activity (≥10% growth inhi- tance to all clinically available BCR-ABL-KIs. The speci- bition). These hits were augmented with available structural ficity was further confirmed by three in vitro findings: (1) analogues and drugs of the same pharmacologic classes to the presence of IL-7 during prolonged dasatinib treatment yield 706 active compounds. Concentration-response rela- significantly increased viability of Arf–/– BCR-ABLWT LICs tionships were established for these compounds against (Suppl. Fig. S5), (2) transient BCR-ABL inhibition dra- BCR-ABLWT and drug-resistant BCR-ABLT315I LICs in the matically increased LIC responsiveness to IL-7 (Suppl. presence of IL-7, giving 229 validated hits with reasonable Fig. S6c,d),13 and (3) removing IL-7 completely reversed potency, representing a final hit rate of 4%. While a high hit the protection effect and restored dasatinib’s potency (data rate, this is congruent with our historical experience screen- not shown). ing this collection in growth inhibitory assays against

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Figure 2. Screen to identify compounds preventing growth of wild-type and BCR-ABLMUTANT Philadelphia chromosome–positive acute lymphoblastic leukemia cells in the presence of interleukin 7. Several hundred validated hits were identified. The hits are shown as a graph with clustering hits using ATC therapeutic classification (http://www.whocc.no/atc/structure_and_principles/). A single compound can be represented more than once because of multiple therapeutic indications, as is the case for the corticosteroids (highly active clusters in A, C, D, H, R, and S). This demonstrates that the active compounds come from drugs used to treat many indications. See supplemental materials and methods and Supplemental Figure S11 for details on clustering methodology and analysis.

cancer cell lines and primary cultures. All validated hits In Vitro and In Vivo Anti–Ph+ ALL WT were equipotent in inhibiting the growth of BCR-ABL Activity of DHA and BCR-ABLT315I LICs, suggesting they are not acting through BCR-ABL. This set included 15 conventional anti- Although our validated hits included compounds with vary- leukemic drugs (see Excel supplement), some of which ing mechanisms of action and compounds in varying stages enhance BCR-ABL-KI therapy in vivo,3,5 thus validating of development, we focused on approved drugs with favor- the detection of appropriate phenotypic responses. able human pharmacokinetic and toxicity profiles that have Furthermore, cluster analysis indicated that this set effec- previously been used with pediatric populations but not for tively sampled the space of all existing therapeutic classes leukemia, which quickly narrowed focus to the artemisinin (Fig. 2). See Excel supplement for a detailed annotation of class of antimalarials (ARTs), which includes artemisinin, validated hits. artesunate, and DHA.14 As a class, the ARTs were equipotent

Downloaded from jbx.sagepub.com by guest on December 19, 2013 Singh et al. 163 against BCR-ABLWT and BCR-ABLT315I LICs (Fig. 3a), but 300 mg/kg), or binary combinations (Fig. 4a). Despite con- the anti-LIC potency of artemisinin (ca. 1 µM EC ) was tinuous monotherapy, dasatinib induced only weak initial 50 weaker than that of artesunate or DHA (ca. 200 nM EC ). responses, and all animals later relapsed (Fig. 4b) with com- 50 DHA and artesunate also killed the human Ph+ ALL cell line plete mortality within 6 weeks of initiating therapy (Fig. 4a). SUP-B15 with similar potency in the presence of IL-7 (Fig. DHA alone was completely ineffective (200 mg/kg) or poorly 3a,b). Studies have shown that DHA kills other genotypes of effective (300 mg/kg) in the high-burden leukemia model leukemic cells while selectively sparing normal human lym- (Fig. 4a). However, the combination of DHA and dasatinib phocytes.15,16 Therefore, DHA was chosen for further analy- provided a strong and rapid initial response and led to signifi- sis because of its potency, cellular selectivity, oral formulation, cantly increased overall survival (Fig. 4a,b) in comparison to favorable pharmacokinetics, known bioavailability in the the treatment with either of the two drugs alone. Of the 12 hematopoietic system, and tolerability in all human age mice given 200 mg/kg DHA and 10 mg/kg dasatinib, 3 sur- groups. vived long term. All mice given 300 mg/kg DHA and 10 mg/ Due to our interest in modeling the approved drug DHA, kg dasatinib (n = 12) survived the treatment period. As dis- which is given orally for malaria, follow-up studies in vivo cussed above, the plasma concentrations expected to be used the oral route rather than the parenteral route more reached with such doses are likely providing exposure well commonly used in oncology studies. DHA monotherapy above that efficacious against LICs and within those that conferred a significant dose-dependent survival benefit to could be reached in humans with good tolerability.17,19 IL-7+/+ host mice bearing low-burden BCR-ABLWT leuke- Four weeks after completion of combination therapy, mia (Fig. 3c), although this required escalation to high one mouse succumbed to an isolated CNS relapse, which doses (300 mg/kg) for maximal effect. During these studies, may be related to the poor CNS availability of dasatinib.20 no significant changes in body weight were observed. This Remarkably, the 14 surviving mice taken off dasatinib- dose falls within the tolerated and bioavailable doses used combined therapy (3/12 at 200 mg/kg and 11/12 at 300 mg/ in prior animal modeling for malaria.17 kg DHA) showed no leukemia for 1 year, the longest period By conventional allometry, this dose corresponds to monitored. In this leukemia model, all animals left untreated roughly 45 mg/kg in a human, which is 4-fold higher than succumbed to full-blown leukemia within 4 weeks of inject- the highest dose used for malaria treatment in humans (up ing very low numbers of LICs (Suppl. Fig. S2), strongly to 12 mg/kg). The limited murine pharmacokinetic data for suggesting that the drug combination cured the disease. All DHA18 indicates that it is more rapidly cleared in mice and dasatinib-DHA regimens were well tolerated in leukemic has lower bioavailability than in humans, suggesting that and nonleukemic mice, with no noticeable changes in lower relative doses would be efficacious in humans. In weight gain or clinical signs, in congruence with prior addition, existing human and murine pharmacokinetic data rodent work using similar dosages of DHA.17 indicate that plasma concentrations that should be achieved in this model would be well above concentrations effica- Discussion cious in vitro against LICs, even at doses more closely aligned with those used for malaria.19 BCR-ABL mutations, We identified IL-7 as the dominant (most potent) cytokine which are often selected with dasatinib treatment in this that confers resistance to all FDA-approved BCR-ABL model,5,7 were absent in leukemic samples collected from inhibitors. IL-7 is essential for murine T-cell and B-cell terminally moribund DHA-treated mice. DHA monother- development,21 has recently been implicated in human post- apy also gave a similar response in mice with low-burden fetal B-cell development,21,22 and is a major contributor to BCR-ABLT315I leukemia, which is completely refractory to the regulation and maintenance of mature T-lymphoid dasatinib (Fig. 3d). Thus, unlike BCR-ABL-KIs, DHA acts cells.23 IL-7–rich niches such as bone marrow harbor early against Ph+ ALL via a BCR-ABL kinase-independent persistent drug-refractory leukemias in dasatinib-treated mechanism. mice, at which point the vast majority of leukemic cells do not harbor BCR-ABL KD mutations.5 Ultimately, BCR- ABL mutations emerge under continuous drug expo- DHA Synergistically Enhances Response 5,24 to Dasatinib sures, causing secondary drug resistance. Our findings suggest that IL-7 maintains leukemic cell viability, proba- Because BCR-ABLWT leukemias in IL-7–deficient mice bly through induction of phosphorylation of STAT5, despite were more sensitive to dasatinib (Fig. 1e), and DHA dis- continuous BCR-ABL inhibition in vivo, thereby facilitat- played anti–Ph+ ALL activity in IL-7+/+ host mice (Fig. 3c,d), ing the subsequent acquisition of drug resistance–confer- the potential for synergy between the two drugs was evalu- ring kinase domain mutations. There is a well-appreciated ated. Cohorts of IL-7+/+ immune-competent mice bearing relationship between phosphorylation of STAT5 and resis- high burdens of Arf–/– BCR-ABLWT –driven leukemia were tance to imatinib in cells.25–27 In addition, human Ph+ ALL treated with dasatinib alone (10 mg/kg), DHA alone (200 or patients with increased levels of pSTAT5, whose

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Figure 3. The artemisinin family of antimalarial drugs circumvents interleukin 7 (IL-7)–induced resistance to dasatinib in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) cells in vitro and Ph+ ALL in IL-7+/+ host mice. (a) Arf –/– BCR- ABLWT (triangles) and Arf –/– BCR-ABLT315I (circles) leukemia-initiating cells (LICs) were treated with artemisinin, artesunate, dihydroartemisinin, or DMSO for 72 h in the absence (blue) or presence (red) of 1 ng/mL murine IL-7, in triplicates. For each drug concentration, LIC growth (measured by the CTG assay) was normalized to DMSO-treated LICs and fit using nonlinear regression (±SD). (b) Human Ph+ ALL SUPB15 cells were treated with artesunate, dihydroartemisinin, or DMSO (no drug) for 72 h in the absence (blue) or presence (red) of 25 ng/mL human IL-7. Viability was measured by the MTS assay. Values were normalized to DMSO-treated cells. (c, d) Kaplan-Meier survival curves showing the overall survival in response to therapy (survival benefit) in IL-7+/+ Bl6 host mice that received day 0 tail vein injection of (c) 2 × 103 Arf–/– BCR-ABLWT Luc+ LICs (on day 3, once daily for 5 days of each week, vehicle, 100 mg/kg DHA, 200 mg/kg DHA, 300 mg/kg DHA, or 300 mg/kg DHA [for 3 weeks only] therapy was initiated in mice bearing low burdens of BCR-ABLWT–driven leukemia) or (d) 2 × 103 Arf–/– BCR-ABLT315I Luc+ LICs (on day 3, once daily for 5 days of each week, vehicle, 300 mg/kg DHA, or 10 mg/kg dasatinib was given to mice bearing low burdens of BCR-ABLT315I–driven leukemia).

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Figure 4. Dihydroartemisinin works synergistically with dasatinib to cure Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). (a) Kaplan-Meier survival curves showing the survival benefit in response to therapy in IL-7+/+ Bl6 host mice that received day 0 tail vein injection of 2 × 105 Arf –/– BCR-ABLWT Luc+ leukemia-initiating cells (LICs). On day 7, six mouse groups bearing high burdens of BCR-ABLWT–driven leukemia were started on daily treatment for 5 days of each week, using two-dose regimens—two vehicles or one vehicle and one agent or two agents (see label), with two doses of each regimen given separately, 8 h apart, by oral gavage. On day 52, all therapy was terminated. (b) For 6 mouse groups in a, separate graphs represent quantitative assessment of serial whole-animal luminescent signals (p/s/cm2/sr) acquired weekly. Solid lines represent imaging intensity of signal (y-axis) as a measure of leukemia burden from individual mice in the group, which is traced in real time on the x-axis. On day 7, before initiating therapy, all six groups had comparable and high burden of leukemia. The horizontal dotted line represents the empirically determined lower limit of sensitivity for luminescent signal as an experimental cutoff for detectable levels of persistent leukemia. Rectangular gray box quantifies experimental primary therapeutic response to indicated regimens; box width depicts approximate time (days) to induce maximal initial response, and box depth represents maximal decrease achieved in leukemia burden signal. Increasing depth and decreasing width indicate stronger and quicker primary responses, respectively. phosphorylation is triggered by IL-7, respond poorly to BCR-ABL inhibition with a second drug that induces IL-7– imatinib therapy.27 independent leukemic cell death. We assayed 5600 com- The demonstration of IL-7–induced drug resistance pro- pounds enriched with approved drugs to identify such vided a rationale for “complementing” pharmacological agents. Our studies confirmed the activities of the majority

Downloaded from jbx.sagepub.com by guest on December 19, 2013 166 Journal of Biomolecular Screening 19(1) of known antileukemia drugs and also identified several high-throughput drug screening, Heather Mulder for performing new classes of the compounds with activity against both BCR-ABL KD mutation analyses, Richard A. Ashmun and Jim IL-7–cultured wild-type and BCR-ABL mutant LICs. We Houston for performing flow cytometric cell sorting and analyses, characterized the antileukemia activity of one such drug: and Owen Witte (UCLA) for the MSCV-BCR-ABL-IRES-GFP the orally bioavailable, well-tolerated, antimalarial agent retroviral vector. DHA, which selectively kills leukemic cells while sparing normal lymphocytes.15,16 Mechanistically, DHA acts inde- Declaration of Conflicting Interests pendently of BCR-ABL-KIs (Fig. 3). In combination with The authors declared no potential conflicts of interest with respect dasatinib, DHA enhanced the depth of remission induction to the research, authorship, and/or publication of this article. (Fig. 4b) and achieved near-complete long-term survival in a robust murine model of human Ph+ ALL. It is noteworthy Funding that the combination of DHA and dasatinib therapy is sig- The authors disclosed receipt of the following financial support nificantly more efficacious than the clinically used triple for the research, authorship, and/or publication of this article: This combination of dasatinib, dexamethasone, and asparaginase work was supported in part by an American Association for when assessed in the same model.5 Cancer Research (AACR) Centennial Career Development Award Distinct from its antimalarial mechanism of action, for Childhood Cancer Research (R.T.W.), NIH 1R21NS066460- induction of cell death by ARTs in transformed cells is asso- 01 (R.T.W. and R.K.G.), Gabrielle’s Angel Foundation Medical Research Award (R.T.W.), NIH/NCI Comprehensive Cancer ciated with accelerating the degradation of c-MYC.28 29 Center Core Grant CA-21765, and the American and Lebanese c-MYC expression is downstream of activated STAT5, Syrian Associated Charities (ALSAC) of St Jude Children’s which is maintained by IL-7 signaling, and STAT5 activa- Research Hospital. tion30 and c-MYC expression31,32 are necessary to sustain BCR-ABL–transformed cells. This phenomenon has References recently been implicated in other stroma-induced drug 1. Bjorkholm, M.; Ohm, L.; Eloranta, S.; et al. Success Story resistance10 as well as used as an explanation for resistance 10,33 of Targeted Therapy in Chronic Myeloid Leukemia: A to imatinib. However, we do not see changes in pSTAT5 Population-Based Study of Patients Diagnosed in Sweden levels in response to treatment with artemisinins (data not from 1973 to 2008. J. Clin. Oncol. 2011, 29, 2514–2520. shown). Thus, DHA may synergize with BCR-ABL-KI 2. Talpaz, M.; Shah, N. P.; Kantarjian, H.; et al. Dasatinib in therapy by accelerating the degradation of c-MYC, thereby Imatinib-Resistant Philadelphia Chromosome–Positive countering the protective effects of IL-7, as has been Leukemias. N. Engl. J. Med. 2006, 354, 2531–2541. reported by others. Alternatively, as has also been reported, 3. Ravandi, F.; O’Brien, S.; Thomas, D.; et al. First Report of DHA may affect BCR-ABL levels directly.34,35 Phase 2 Study of Dasatinib with Hyper-CVAD for the Frontline We have shown that phenotypic screening using primary Treatment of Patients with Philadelphia Chromosome– leukemia cells selected to maintain responsiveness to host Positive (Ph+) Acute Lymphoblastic Leukemia. Blood 2010, cytokines allows identification of therapeutic agents or 116, 2070–2077. 4. Nicolini, F. E.; Mauro, M. J.; Martinelli, G.; et al. Epidemiologic developmental compounds that hold promise for the treat- Study on Survival of Chronic Myeloid Leukemia and Ph(+) ment of Ph+ leukemias. This system provides an unbiased Acute Lymphoblastic Leukemia Patients with BCR-ABL platform for the discovery of such new therapies and to T315I Mutation. Blood 2009, 114, 5271–5278. evaluate the potential utility of such agents by demonstrat- 5. Boulos, N.; Mulder, H. L.; Calabrese, C. R.; et al. ing proof of concept in vivo using a murine model that Chemotherapeutic Agents Circumvent Emergence of closely recapitulates human disease. Finally, our results Dasatinib-Resistant BCR-ABL Kinase Mutations in a Precise strongly support further study of BCR-ABL-KI/DHA com- Mouse Model of Philadelphia Chromosome–Positive Acute bination therapy for the treatment of patients with high-risk Lymphoblastic Leukemia. Blood 2011, 117, 3585–3595. Ph+ ALL. 6. Williams, R. T.; den Besten, W.; Sherr, C. J. Cytokine-Dependent Imatinib Resistance in Mouse BCR-ABL+, Arf-Null Lymphoblastic Leukemia. Genes Dev. 2007, 21, 2283–2287. Acknowledgments 7. Williams, R. T.; Sherr, C. J. The INK4-ARF (CDKN2A/B) We acknowledge Charles J. Sherr, Gerard Zambetti, and Joe Locus in Hematopoiesis and BCR-ABL–Induced Leukemias. Opfermann for critically reading the manuscript. We thank Cold Spring Harb. Symp. Quant. Biol. 2008, 73, 461–467. Chandra Savage and Branden Williams for assistance with mouse 8. Snead, J. L.; O’Hare, T.; Adrian, L. T.; et al. Acute Dasatinib therapeutic studies, Christopher R. Calabrese and Monique Payton Exposure Commits Bcr-Abl–Dependent Cells to Apoptosis. for assistance with animal imaging, Alexander J. Kovalic and Per Blood 2009, 114, 3459–3463. Holmfeldt for assistance with in vitro growth factor screening 9. Kim, H. P.; Frankel, A. E.; Hogge, D. E. A Diphtheria Toxin experiments, Narendra P. Singh for suggestions on drug prepara- Interleukin-3 Fusion Protein Synergizes with Tyrosine Kinase tion for animal use, Armand Guiguemde and Jimmy Cui at the Inhibitors in Killing Leukemic Progenitors from BCR/ABL High Throughput Screening Center at St. Jude for assistance with Positive Acute Leukemia. Leukemia Res. 2010, 34, 1035–1042.

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Downloaded from jbx.sagepub.com by guest on December 19, 2013 Supplementary Information (PDF)

A screening based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia Harpreet Singh 1┼, Anang A. Shelat 2, Amandeep Singh 3, Nidal Boulos 1, Richard T. Williams 1┼†, R. Kiplin Guy 2┼* 1Department of Oncology, 2Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105 3Department of Medicine, Kings County Hospital Center, 451 Clarkson Avenue, Brooklyn, NY, 11203 ┼Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, 920 Madison, Memphis, TN, 38103 †Current address: Puma Biotechnology Inc., Los Angeles, CA 90024

* For Correspondence: Kip Guy, Ph.D Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678. Tel: 901-595-5714, Fax: 901-595-2715, Email: [email protected]

This Supplementary Information (PDF) section comprises of table of contents; materials and methods for FACS assessment of viability; FACS assessment of cell cycle percentages; drug/cytokine washout and cytokine recovery studies; dasatinib re-challenge studies; detailed description of chemical library screened; HT drug screens - data processing, quality control and hit scoring criteria; cluster analysis of hits using therapeutic drug classes; Supplementary Figures S1-S11 with legends; Supplementary Table 1 and Supplementary References.

Page 1 of 24 Supplementary Information - Singh, et al. Table of contents for Supplementary Information (PDF):

Production and culture of murine leukemia initiating cells (LICs) ...... 3 In vivo adoptive leukemia transfer Ph+ ALL model ...... 3 FACS assessment of viability ...... 4 FACS assessment of cell cycle percentages ...... 4 Detailed description of chemical library screened ...... 6 Data processing, quality control and hit scoring criteria for HT drug screens ...... 7 In vivo preclinical therapeutic studies ...... 10 Bioluminescent imaging and evaluation of cures ...... 10 Supplementary Figure S1: ...... 11 Supplementary Figure S2: ...... 12 Supplementary Figure S3: ...... 13 Supplementary Figure 4: ...... 14 Supplementary Figure 5: ...... 15 Supplementary Figure 6: ...... 16 Supplementary Figure S9: ...... 20 Supplementary Figure S10: ...... 21 Supplementary Figure S11: ...... 22 Supplementary Table 1: ...... 23 Supplementary References ...... 25

Page 2 of 24 Supplementary Information - Singh, et al. Production and culture of murine leukemia initiating cells (LICs) Replication-defective mouse stem cell virus (MSCV) retroviral vectors co-expressing either the wild-type (WT) allele of human p185 BCR-ABL or mutant BCR-ABL alleles p185 T315I or p185 F317L , and either green fluorescent protein (GFP) or luciferase, were packaged into replication-incompetent ecotropic virions[17,18,22]. Whole bone marrow cell suspensions from

Arf -/- young adult mice were transduced to produce Arf -/- p185+ pre-B LICs [17,22]. After initial establishment on autologous stromal cell layers over 7 days, transformed pre-B cells were briefly expanded in the absence of a stromal layer for 2 days in liquid culture in BCM10 media

(RPMI1640 supplemented with 10% Hyclone fetal calf serum, 4 mM glutamine, 100 Units/mL penicillin, 100 µg/mL streptomycin, and 55 µM beta-mercaptoethanol[18]), and cryopreserved.

Prior to use in any assays, Arf -/- p185 WT and Arf -/- p185 T315I pre-B cells (BCR-ABL WT LICs and

BCR-ABL T315I LICs, respectively) were thawed and allowed to recover and expand exponentially in BCM10 for 3 days.

In vivo adoptive leukemia transfer Ph+ ALL model Mice were housed in an American Association of Laboratory Animal Care (AALAC)– accredited facility and treated on Institutional Animal Care and Use Committee (IACUC)– approved protocols in accordance with NIH guidelines. Adoptive cell transfers were performed by injecting LICs into tail veins of healthy, non-conditioned, immune-competent 10- to 12-week- old IL-7+/+ or IL-7-/- C57Bl/6J mice (Jackson Labs, Bar Harbor, ME). Animals were observed daily and sacrificed when moribund (dehydration, ruffled fur, poor mobility, respiratory distress). Survival curves were generated using GraphPad Prism Version 5.0 (La Jolla, CA). The

Mantel-Cox test was applied to pairwise comparisons of survival data.

Page 3 of 24 Supplementary Information - Singh, et al. FACS assessment of viability Viability of LICs was estimated after counterstaining approximately 5 x 10 5 LICs (in 0.5 mL volume) with 35 µL of a propidium iodide (PI) solution (0.25 mg/mL in PBS). The percentage of viable cells was calculated by electronic gating on PI-negative cells on PI versus forward scatter dot plots, with forward scatter signals consistent with LICs, and comparison of this number with total cell number. Data were collected and analyzed on a BD Biosciences LSR II flow cytometer

(San Jose, CA), using BD Biosciences FACS DiVa software.

FACS assessment of cell cycle percentages For determination of percentages in cell cycle phases, 5 x 10 5 LICs were centrifuged, washed once with PBS, recentrifuged, and cell pellets were resuspended in 0.5 mL PI staining solution

(0.05 mg/mL PI, 0.1% sodium citrate, 0.1% Triton X100), which lysed the cells and stained nuclear DNA with PI. Samples were then treated with DNAse-free RNAse (0.2 mg/mL in 10 M

Tris-HCl/15 mM NaCl, pH 7.5) for 30 min at room temperature, filtered, and analyzed for red fluorescence from a PI-labeled DNA on BD Biosciences FACS Calibur flow cytometer (San

Jose, CA) by using BD Biosciences CellQuest Pro software. The percentages of cells within each cell cycle phase were computed using the computer program ModFit (Verity Software House,

Topsham, ME). Drug/cytokine washout and cytokine recovery studies

For washout studies, BCR-ABL WT LICs were diluted to a density of 1 × 10 5 LICs/mL in BCM-

10 containing no or 5 mg/mL IL7, and treatment with either dasatinib or 0.1% DMSO by volume

(non-drug treated controls) was initiated at time 0 h in triplicate 100 mm petri dishes. Daily monitoring for expected drug-induced changes was performed by naked-eye microscopy from 0 to 72 h. At the 72 h time point, after harvesting under identical conditions, total LIC density and viability percentage for all samples were determined using Beckman Coulter Vi-cell (trypan

Page 4 of 24 Supplementary Information - Singh, et al. blue) in triplicates. Each sample was spun down in 50 mL BD Falcon™ tubes; the supernatant was discarded and LIC pellet resuspended in freshly prepared BCM-10 (not containing any cytokine or drug). This washing step was repeated 4 times to ensure complete removal of the drug and/or cytokine. After the last wash, each pellet was resuspended to 1 × 10 6 total LICs per mL master stocks. Aliquots from master stocks were taken for (i) flow assessment of viability and cell cycle percentages (as described above); (ii) manual CTG assay using 25 uL sample per well in 384-well microplates (in triplicates), as an independent determination for LIC growth.

For assessment of extracellular cytokine on recovery of LICs that were previously challenged with dasatinib (0 to 72 h), washed master stocks were diluted to 5 × 10 5 total LICs per mL in

BCM10 with or without 5 ng/mL IL7, plated in 6 well plates (10 cm 2 approx), and incubated at

37 °C from 72 to 144 h for recovery, during which time daily naked-eye microscopic examinations were performed. At 144 h, for each sample total LIC density and viability percentage assessment by Beckman, viability and cell cycle percentages by flow assessment and independent CTG evaluations were performed as described for the 72 h time point. Cell growth trends by CTG readout corroborated the findings from trypan blue (Beckman) and DAPI staining

(FACS). Key results are presented in Supplementary Figure S6; total viable LICs in a sample were calculated as a product of absolute LIC count determined by Beckman and absolute sample viability determined by FACS analysis. Dasatinib re-challenge studies

Further studies were performed to evaluate the possibility of a genetically drug-resistant subpopulation that could undergo selection with dasatinib/IL7 co-treatment during 0-72 h of dasatinib/cytokine washout studies above. To this aim, BCR-ABL WT LICs were treated with 100 nM dasatinib or 0.1% DMSO in the absence or presence of 5 ng/mL IL7 in 100 mm dishes from

0-72 h, as described above; in addition, a dasatinib challenge (first-time challenge) across 6 log-

Page 5 of 24 Supplementary Information - Singh, et al. fold concentration in the presence or absence of 5 ng/mL IL7 was also performed using CTG assay during this time period (0-72 h). At 72 h, dasatinib/IL7 co-treated LICs from 100 mm dishes were washed (as described above) and immediately challenged (second challenge) from

72 to 144 h with six log-fold concentration range of dasatinib in 384-well microplates either in the presence or absence of 5 ng/mL IL7 using CTG assay. At 144 hrs, dasatinib showed similar potency against LICs in the absence of IL7, irrespective of previous dasatinib exposure.

Furthermore, potency of dasatinib was blunted, to a similar extent, during both the first and second drug challenges only when extracellular IL7 was present (data not shown).

Detailed description of chemical library screened The screening library consisted of 5600 (approximately 3200 unique) approved drugs and chemicals with known biological activity (bioactives). The library was assembled from 3 commercial suppliers: Microsource, Prestwick, and Sigma. The Microsource compounds included the following: (a) the Spectrum collection, which contains 2000 biologically active and structurally diverse compounds, including known drugs, experimental bioactives, and pure natural products(1, 2); (b) the US Drug Collection, which contains 1040 drugs that have reached clinical trials in the US and have been assigned USAN or US Pharmacopeia status; and (c) the

Killer collection, which contains a reference set of 160 synthetic and natural toxic substances

(http://www.msdiscovery.com/index.html ). The Prestwick compounds include 1120 small molecules selected for high chemical and pharmacologic diversity. Ninety percent of the collection is composed of known marketed drugs, and the remainder includes bioactive alkaloids or related substances. Human bioavailability and human toxicity data are available for most compounds ( http://www.prestwickchemical.fr/index.php?pa=26 ). The Sigma LOPAC1280

(Library of Pharmacologically Active Compounds) collection reflects the most commonly

Page 6 of 24 Supplementary Information - Singh, et al. screened targets in the drug discovery community, including marketed drugs, failed development candidates, and "gold standards" that have well-characterized activities

(http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html ).

Data processing, quality control and hit scoring criteria for HT drug screens All data processing and visualization was performed using custom programs written in the

Pipeline Pilot platform (Accelrys, v.7.5) and the R program 6.6(3, 4). The R drc package was used to fit sigmoidal curves(4). ROC statistics were computed using the ROCR package(5).

The quality of the primary drug-screening studies, performed in parallel against BCR-ABL WT and BCR-ABL T315I LICs, was evaluated by multiple methods including, but not limited to, identification of known antileukemic agents, identification of multiple compound replicates intentionally included in the 5600 collection, and Z’ and other screening quality metrics

(described in Supplementary Figures S7 to S10 ). In the screening experiments, all assay plates demonstrated attenuation of dasatinib potency in presence of IL7 or BCR-ABL mutation, similar to results described in Figure 1a and 1b. An empirically determined, statistically significant but liberal cut-off of >10% activity was chosen to include agents of relatively lower activity considering the high-risk nature of Ph+ ALL and the drug-rich nature of the library as well as to allow for a more complete structure-activity relationship and therapeutic class analysis after subsequent potency determination through secondary screening

The discriminatory power of the phenotypic assay was assessed using receiver operating characteristic (ROC) statistics. A total of 165 compounds were selected to sample the primary assay according to the distribution of observed activities. ROC curves are shown in

Supplementary Figure S10 . The assay has good discriminatory power; with similar AUCs of

Page 7 of 24 Supplementary Information - Singh, et al. approximately 0.83 and 0.85 against BCR-ABL WT and BCR-ABL T315I LICs, respectively (an ideal assay has an AUC of 1.0, whereas a random assay has an AUC of 0.5).

The activity class designations in the Excel Supplement were assigned based on the curve score and visual inspection of dose-response curves. The curve score is a 4 character code derived from the following heuristic:

• First character: letter (A,B,C or D) indicating curve quality

o D = less than 2 points above the noise (defined as outliers from the negative

control population)

2 o C = r < 0.50 or range > 200% or EC 50 > maximum concentration tested

o A = r 2 > 0.80 and difference between two last points < 10% (indicating saturation)

o B = not A,C, or D

o N prefix = activity decreases with increase concentration

• Second character: number (1-6) indicating potency

o 1 = EC 50 < 0.1 µM

o 2 = 0.1 µM ≥ EC 50 < 1.0 µM

o 3 = 1.0 µM ≥ EC 50 < 10.0 µM

o 4 = EC 50 > 10.0 µM

o 5 = all C and D curves are assigned 5

• Third character: number (1-6) indicating efficacy

o 1 = 75% ≥ range < 200%

o 2 = 50% ≥ range < 75%

o 3 = 25% ≥ range < 50

o 4 = range < 25%

Page 8 of 24 Supplementary Information - Singh, et al. o 5 = all C and D curves are assigned 5

• Fourth character: number (1-6) indicating hill slope

o 1 = hill ≤ 2

o 2 = 2 < hill ≤ 4

o 3 = 4 < hill ≤ 8

o 4 = hill > 8

o 5 = all C and D curves are assigned 5

A complete list of all compounds evaluated in the secondary drug-screening experiments with their structure, supplier information, synonyms, EC50 values, and therapeutic classification is reported in the Excel Supplement .Cluster analysis of hits using therapeutic classes

The therapeutic cluster graph was generated by first assigning each compound an Anatomical

Therapeutic Chemical Classification System (ATC). This classification system groups drugs into a 5 level hierarchy according to therapeutic indication and chemical properties. The first level indicates anatomical main group and consists of 1 letter; the second level indicates therapeutic main group and consists of 2 digits; the third level indicates therapeutic or pharmacological subgroup and consists of 1 letter; the fourth level indicates chemical, therapeutic or pharmacological subgroup and consists of one letter; and the fifth level indicates the chemical substance and consists of 2 digits. The resulting 7 characters constitute an ATC code, and a compound can be assigned multiple ATC codes. ATC codes can be depicted as a network graph by defining a node to represent each level in the ATC code and then connecting nodes according to parent-child relationships (e.g., first-level node A is the parent of second level nodes A01, A02, etc.). Compounds without an ATC code were assigned based on similarity to known agents, or were assigned to custom codes located under the parent V99

Page 9 of 24 Supplementary Information - Singh, et al. (labeled as “Not defined in ATC” in Figure 2). See Supplementary Figure 10 for the frequency of ATC Level 1 and Level 2 codes among the 706 compounds submitted to dose-response analysis.

The resulting network was visualized in Cytoscape (v 2.8.1) using the yFiles circular layout algorithm(6). The cytoscape file for this network is available for download as part of this supplement.

In vivo preclinical therapeutic studies For in vivo use, dasatinib (LC Labs, Woburn, MA) in citric acid (pH 3.1) [25], and DHA

(Avachem, San Antonio, TX) in 0.5% carboxy-methylcellulose/0.5% Tween 80/0.5% benzyl alcohol, were administered by oral gavage. In toxicity studies (data not shown), DHA was ranged up to 300 mg/kg as a single or split dose for 5 days/week over a six week time period.

Repeated single doses of 300 mg/kg (5 days/week) were determined to induce no significant weight loss, lethargy, seizures or deaths [26]. During therapeutic studies, animal weights were monitored daily to ensure no significant body weight reductions.

Bioluminescent imaging and evaluation of cures Bioluminescent imaging and analysis were performed using a Xenogen IVIS-200 system and Living Image software 3.01 (Caliper Life Sciences, Hopkinton, MA)[17]. Total bioluminescent flux measurements (photons/second) were quantified over the whole animal body. Recipient mice that remained clinically healthy 12 months after terminating therapy and had no detectable bioluminescent signal in vivo were designated “long-term survivors.”

Page 10 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S1: Comparison of the growth properties of Arf -/- p185 WT (filled symbols) and Arf -/- p185 T315I preB (empty symbols) populations during in vitro cell culture.

Both cell types were plated at multiple cell dilutions (n=3 for each condition, time=0 h) in 6-well plates and serially followed daily for 5 days to evaluate absolute viable cell count, total viability, doubling times, and total population doublings, using the Beckman Coulter cell counter

(trypan blue staining) and fluorescence-activated cell sorting (FACS) analysis in parallel. Both cell types had identical growth properties. Only the comparison for population doubling time in hours (+/- sd) for 3 relevant plating densities is presented. FACS cell-cycle analysis confirmed that a population doubling time less than 14 h was sufficient to maintain cells in exponential growth (>50% cells in S-phase).

Page 11 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S2: Leukemia stem cell function (LSC) function assay by serial dilution and implantation comparing the in vivo leukemia initiating capacity of Arf -/- p185 WT

(left) and Arf -/- p185 T315I preB (right) populations. Kaplan-Meier curves represent the overall survival of nonconditioned immunocompetent C57Bl/6J recipient mice that received serial log- fold dilutions (n=4 per arm) of LIC-number (as indicated in the inset legend) on day 0. Arf -/- p185-transformed preB murine cells are hereafter referred as LICs.

Page 12 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S3: Optimization of the high-throughput LIC-based phenotypic assay. BCR-ABL WT LICs plated at 5 × 10 4 per mL were challenged with 6 log-fold concentration range of dasatinib or DMSO in 384-well microplates. After a 72 h drug challenge, LIC growth was measured by 3 cellular readouts: CellTiter-Glo (CTG) assay (ATP content), MTS assay

(viability), and high-throughput flow cytometry (total viability and viable cell counts by DAPI exclusion). Measured assay readouts at various drug concentrations (x-axis) were normalized to

DMSO-treated LICs and graphed (+/- sd) on y-axis. Total viable LIC counts were determined by

FACS, reflecting dasatinib-induced phenotypic changes across a 6 log-fold drug-concentration, were closely paralleled by the CTG cellular assay output but not by the commonly used MTS assay.

Page 13 of 24 Supplementary Information - Singh, et al.

Supplementary Figure 4: Comparative evaluation of IL7-mediated protection conferred against non-BCR-ABL–specific targeting drugs (top panel) and conventional cytotoxic antileukemic clinical drugs (bottom panel). BCR-ABL WT LICs were treated with indicated drugs or DMSO (no drug) for 72 h in the absence (blue) or presence (red) of high (10 ng/mL) murine

IL7, in triplicates. The antibiotic drug Cefaclor (often used in leukemia clinics) was used as a non-antileukemic drug control. For each drug concentration, LIC growth was measured by the

CTG assay and average values were normalized to DMSO-treated LICs and graphed (+/- sd).

Page 14 of 24 Supplementary Information - Singh, et al.

Supplementary Figure 5: In vitro leukemia clonal outgrowth efficiency assays. Either 1 or 10 viable BCR-ABL WT LICs per well sorted by single-cell flow cytometry into 3 clear-bottom

384-well plates for each condition (n=1152) were treated (t=0) with DMSO (0.1 % by volume) or dasatinib in the absence (black) or presence (grey) of IL7 (10 ng/mL). After 8 days of incubation, naked-eye microscopic examination was performed. Wells showing significant positive growth (approximately ≥50 LICs per well) were scored positive and percentage of positive wells for each condition indicated on the x-axis was calculated.

Page 15 of 24 Supplementary Information - Singh, et al.

Supplementary Figure 6: Protection of BCR-ABL WT LICs by IL7 during dasatinib exposures (0 to 72 h) and in the post-exposure recovery period (72 to 144 h, no dasatinib) . See

Supplementary Methods above for details. ( a) Total sample viabilities (DAPI staining, FACS) at the end of exposure period (dark gray=IL7; light gray=No IL7) and recovery period (red=IL7; blue=No IL7). Light gray vs. dark gray comparison depicts significant IL7 protection during dasatinib exposures. Few LICs surviving dasatinib exposures in the absence of IL7 (light gray), later deteriorated and died during recovery period, irrespective of IL7, confirming that BCR-

ABL inhibitor exposures commit BCR-ABL+ cells to death(7). IL7 significantly improved recovery of dasatinib/IL7 co-treated LICs (red vs blue), clearly evident at 1000 nM but not at

100 nM and 10 nM dasatinib concentration because of over-confluent growth in presence of IL7

Page 16 of 24 Supplementary Information - Singh, et al. (see Methods, (c) and (d)). ( b) Cell cycle changes (FACS) at the end of exposure period

(corresponding to light and gray bars in (a)). Incremental dasatinib doses (which cause incremental BCR-ABL inhibition(8)) induced cell cycle arrest and apoptosis; IL7 significantly protected LICs from these changes ( c) Cell cycle analysis at the end of recovery period

(corresponding to blue and red in (a)). ( d) Conditions showing positive LIC growth during recovery period, normalized for equal number of LICs plated at start of recovery (dark grey).

Ratio of fold LIC-change in presence (face-down bracket) to that in absence (face-up bracket) of

IL7 increased in LICs with higher previous BCR-ABL inhibition from higher dasatinib concentrations during exposure period.

Page 17 of 24 Supplementary Information - Singh, et al. Supplementary Figure S7: Quality control for the primary screen of 5600 agents against

BCR-ABL WT LICs performed in the presence of 0.85 ng/mL IL7. See Supplementary table1 for well locations. ( a) Distribution of EC 50 of non-BCR-ABL–inhibiting reference compound staurosporine (calculated from wells 2A-2J in (d)). ( b) Scatter plot of percent activity of the test compounds relative to controls. Good separation is seen between negative controls (red, DMSO- treated. max signal, column 13 in (d)) and positive controls (green, 300 nM staurosporine, min signal, column 14 in (d)). Test compounds showing statistically significant activity relative to background noise (negative controls, red) are depicted in blue and inactive test compounds in black. Densities for positive, negative, and test compounds are shown on the right. ( c)

Distribution of Z’ values for each plate in the primary screen. All Z’ values throughout the run – average=0.82, lowest=0.71 and highest=0.9 ( d) Heat map comparison of well activity averaged across all plates. Wells 1A-1J and 2A-2J show serial dilutions of dasatinib and staurosporine. In presence of IL7, average LIC growth inhibition of approx. 45% was achieved by 100 nM dasatinib (well 1A), the later approaching maximum concentration achieved in human plasma.

Page 18 of 24 Supplementary Information - Singh, et al. Supplementary Figure S8: Quality control for primary screen of 5600 agents against

T315I BCR-ABL LICs performed in the presence of 0.85 ng/mL IL7. (a) Distribution of EC 50 of non-BCR-ABL–inhibiting reference compound staurosporine (calculated from wells 2A-2J in

(d)). ( b) Scatterplot of percent activity of the test compounds relative to controls. Good separation is seen between negative controls (red, DMSO-treated, max signal, column 13 in (d)) and positive controls (green, 300 nM staurosporine, min signal, column 14 in (d)). Test compounds showing statistically significant activity relative to background noise (negative controls, red) are depicted in blue; inactive test compounds are black. ( c) Distribution of Z’ values for each plate in the primary screen. All Z’ values throughout the run – average=0.85, lowest=0.77, and highest=0.92 ( d) Heat map comparison of well activity averaged across all plates. Wells 1A-1J and 2A-2J show serial dilutions of dasatinib and staurosporine tested against BCR-ABL T315I LICs. Although 100 nM dasatinib (Well 1A) was totally ineffective, well

2A with highest staurosporine concentration (300 nM) showed average LIC growth inhibition of approximately 100%.

Page 19 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S9: Primary high-throughput drug screening experiments capture

BCR-ABL-KI drug-resistant phenotypes with high accuracy. Distributions of independent dose response curves of dasatinib and staurosporine against BCR-ABL WT and BCR-ABL T315I LICs in the presence of 0.85 ng/mL IL7 calculated separately from all assay plates (wells 1A-1J and 2A-

2J) of primary drug screening experiments (also see Supplementary Fig. S7d and S8d) are

WT presented. Both IL7-imparted dastinib–resistant phenotype in BCR-ABL LICs (EC 50 in nM:

95%CI = 86-116, average >100) and BCR-ABL-mutation-imparted BCR-ABL-KI–resistant phenotype in BCR-ABL T315I LICs, similar to Figure 1b, were consistently captured across all plates. Low interplate variability in calculated EC50 values was observed for the non-BCR-ABL- targeting reference compound staurosporine (95%CI for EC 50 in nM: WT = 11-12, T315I = 15-

16) and majority of the validated hits (refer the Excel Supplement ).

Page 20 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S10: Receiver Operating Characteristic (ROC) analysis demonstrates that both (a) BCR-ABL WT and (b) BCR-ABL T315I LIC-based assays have high discriminatory power (AUC 0.83 and 0.85, respectively). The ROC curve is plotted as a function of % activity, and is color coded according to the right Y-axis. The ROC curves in gray are calculated from 200 bootstrap simulations. The dashed line corresponds to a random assay.

Page 21 of 24 Supplementary Information - Singh, et al.

Supplementary Figure S11: Frequency of ATC Level 1 (top) and ATC Level 2 (bottom) compounds for the 706 compounds submitted to secondary analysis.

Page 22 of 24 Supplementary Information - Singh, et al. Supplementary Table 1: Steps in optimized high-throughput screening assay (CTG readout)

Step Parameter Value Description

1 Plate cells 25 µL Plate LICs 5 x 10 4 per mL (25 µl/well) in BCM10 + 0.85 ng/mL IL7 into 384-well opaque bottom white microplates using Wellmate (Matrix)

2 Primary drug 25 nL 1A-1I: Nine dasatinib concentrations (100 nM, 30 nM, 10nM, 3 nM, 1 nM, 0.3 screening nM, 0.1 nM, 0.03 nM and 0.01 nM) – control for IL7- and BCR-ABL mutation- controls in imparted resistance against BCR-ABL-KIs columns 1-2 and 13-14 2A-2I: Nine staurosporine concentrations (300 nM, 100 nM, 60 nM, 30 nM, 10 nM, 6 nM, 3 nM, 1 nM, 0.6 nM)– non-BCR-ABL-specific reference control in the presence of IL7

13A-13P, 1J, 2J: DMSO 0.1% (Max Signal OR Negative Control); 14A-14P: staurosporine at 300 nM (Min Signal OR Positive Control); 1K-1P, 2K-2P: 40 µM

dasatinib

Secondary drug 21A-21P: DMSO 0.1% (Max Signal); 22A-22P, 23K-24P, 24K-24P: staurosporine screening 25 nL at 300 nM (Min Signal) controls in columns 21-24 23A-23J: Staurosporine – 10 log-fold dilutions (3 µM to 0.3 pM) - non-BCR- ABL–specific reference control in the presence of IL7

24A-24J: Dasatinib – 10 log-fold dilutions (1 µM to 0.1 pM) – control for IL7- and BCR-ABL mutation-imparted BCR-ABL–KI drug-resistance

3 Add test 25 nL Primary screening: Single final drug concentration of 10 µM compounds in columns 3-12 Secondary screening: Triplicate ten half-log serial dilutions (5 µM to 2 nM final and 15-24 in concentration) of primary screening hits to determine their half-maximal inhibitory primary; concentrations (IC 50 ) against LICs columns 1-20 in secondary 384-well master drug-stock plates prepared at 1000X in DMSO. Drug delivered to screen assay plates by pin transfer (using V&P Scientific pin tool, 10H pins), giving a final drug concentration of 1× and 0.1% DMSO in all control and test wells of assay plates

o 4 Incubation 1 72 h Liconics incubator, 8%CO 2, 37 C (standard LIC culture conditions)

5 Incubation 2 20 min Room temp, low light (instructions as per Promega)

6 Add reagent 25 µL CellTiter Glo (Promega) pre-equilibrated to RT before use

7 Incubation 3 25 min Room temp, low light (per Promega)

8 Assay readout ATP Envision, Luminescent mode – ATP levels as a measure of LIC number and viable levels growth in 72 h – Signal measured in RLUs

9 Data processing Pipeline % inhibition by test compound = 100 * (Log 10 Test Signal – Log 10 Min Signal Pilot mean)/( Log 10 Min Signal mean – Log 10 Max Signal mean) Z-prime ( Z’) = 1-[(3*stdev of Log 10 Max Signal + 3*stdev of Log 10 Min Signal)/( Log 10 Max Signal mean - Log 10 Min Signal mean)] Z’is a dimensionless calculation

Page 23 of 24 Supplementary Information - Singh, et al. to assess assay quality - for a good assay Z’≥ 0.5, and for a perfect assay Z’= 1

Page 24 of 24 Supplementary Information - Singh, et al. Supplementary References 1. Kocisko DA, Baron GS, Rubenstein R, Chen J, Kuizon S, Caughey B. New inhibitors of scrapie-associated prion protein formation in a library of 2000 drugs and natural products. J Virol 2003;77(19):10288-94. 2. Weissmann C, Aguzzi A. Approaches to therapy of prion diseases. Annu Rev Med 2005;56:321-44. 3. Team RDC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2009. 4. Ritz C, Streibig JC. Bioassay Analysis using R. J Statist Software 2005;12 (5)(5):22. 5. Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: visualizing classifier performance in R. Bioinformatics 2005;21(20):3940-1. 6. Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 2011;27(3):431-2. 7. Snead JL, O'Hare T, Adrian LT , et al. Acute dasatinib exposure commits Bcr-Abl- dependent cells to apoptosis. Blood 2009;114(16):3459-63. 8. Luo FR, Yang Z, Camuso A , et al. Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res 2006;12(23):7180-6.

Page 25 of 24 Supplementary Information - Singh, et al. Worksheet Description Legend Notes * hostFactor : cytokine name Triplicate measurements were pooled and fit to a * conc : cytokine concentration single curve using a two parameter logistic model The effect of 15 leukemia- (bottom fixed to 0% and top fixed to 100%) microenvironment relevant cytokines on * hill : hill slope Host Factors * EC 50 : dasatinib EC 50 (nM) dasatinib potency (EC 50 ) against Arf-/- BCR-ABLWT LICs * EC 50 CI := EC 50 95% confidence interval * r2: r-squared of the non-linear regression * sample : St. Jude registration number (regnumber + batch number) * regnumber: St. Jude registration root number * supplier name : name of the chemical supplier for this compounds * supplier ID : vendor unique identifier * salt name : name of any salt present Structural information for 706 Structure * salt eqs. : number of salt equivalents compounds * solvate name : name of any solvate present * solvate eqs. : number of solvate equivalents * formula weight : total molecular weight of all species present in the sample * molsmiles : molecular SMILES * synonym : alternate names for this compound * Name of clinical anti-leukemic agent * Conventional anti-leukemic agents - Cladribine,

WT_EC 50 : mouse wild-type BCR-ABL B-cell EC 50 ( µM) Clofarabine, Decitabine, Fludarabine, Nelarabine and Pentostatin, all of which are nucleoside * WT_EC 50 CI : WT EC 50 95% confidence interval * WT_actclass : WT activity classification analogs/antimetabolites, were originally not * WT_curveScore : grade for quality of the WT dose-response curve (see Supplemental for present among agents tested; many agents with List of 15 clinically-used conventional similar MOA were validated. Other details) Screen Summary (1) anti-leukemic agents validated during clincal anti-leukemic agents which belong to * T315I_EC : mouse T315I BCR-ABL B-cell EC ( µM) dose-response screening experiments 50 50 categories - antibody, growth factors, enzymes or * T315I_EC50CI : T315I EC50 95% confidence interval oligonucleotides, are not compatible to HTS and * T315I_actclass : T315I activity classification were not present in the tested compound library. * T315I_curveScore : grade for quality of the T315I dose-response curve (see Supplemental for details)

* WT_EC 50 : mouse wild-type BCR-ABL B-cell EC 50 ( µM) A few compounds showed differential activity between WT and T315I. Most of these are * WT_EC 50 CI : WT EC 50 95% confidence interval * WT_actclass : WT activity classification annotated with "Differential activity within * WT_curveScore : grade for quality of the WT dose-response curve (see Supplemental for experimental error", indicating that there was details) sufficient uncertainty in the curve fit or that the differences are a result of the hard cutoffs applied Complete dose-response screening * T315I_EC : mouse T315I BCR-ABL B-cell EC ( µM) Screen Summary (2) 50 50 for activity classification and are not significant. data for 706 compounds * T315I_EC50CI : T315I EC50 95% confidence interval * T315I_actclass : T315I activity classification * T315I_curveScore : grade for quality of the T315I dose-response curve (see Supplemental for details) * comment : comments on - observed differential activity * ATC_L1 : Anatomical Therapeutic Chemical (ATC) Classification System first level (anatomical main group) * ATC_L2 : Anatomical Therapeutic Chemical (ATC) Classification System second level (therapeutic main group) ATC Classification ATC classification for 706 compounds * ATC_L3 : Anatomical Therapeutic Chemical (ATC) Classification System third level (therapeutic/pharmacological subgroup) * ATC_L4 : Anatomical Therapeutic Chemical (ATC) Classification System fourth level (chemical/therapeutic/pharmacological subgroup) 2 hostFactor conc hill EC 50 EC 50 CI r IL3 0.0 ng/ml 0.5391 5.1118 3.8724 - 6.7479 0.987 IL3 0.01 ng/mL 0.4619 7.5159 5.4628 - 10.3405 0.983 IL3 0.1 ng/mL 0.3164 22.1664 12.1764 - 40.3525 0.944 IL3 1 ng/mL 0.3553 23.3197 14.1087 - 38.5443 0.958 IL3 10 ng/mL 0.3911 22.5621 14.9315 - 34.0924 0.971 IL3 100 ng/mL 0.4276 21.5773 15.2841 - 30.4619 0.979 IL15 0.0 ng/ml 0.5374 4.5252 3.4241 - 5.9805 0.987 IL15 0.01 ng/mL 0.5456 4.7956 3.6317 - 6.3325 0.987 IL15 0.1 ng/mL 0.5223 5.1369 3.9508 - 6.6792 0.988 IL15 1 ng/mL 0.5639 4.6853 3.4341 - 6.3924 0.984 IL15 10 ng/mL 0.5474 4.8593 3.7109 - 6.3630 0.987 IL15 100 ng/mL 0.5803 4.2075 3.2656 - 5.4211 0.989 IL6 0.0 ng/ml 0.5269 4.5635 3.2798 - 6.3497 0.982 IL6 0.01 ng/mL 0.5395 4.6483 3.4190 - 6.3197 0.984 IL6 0.1 ng/mL 0.5771 4.2131 3.1209 - 5.6876 0.984 IL6 1 ng/mL 0.5312 4.645 3.4403 - 6.2716 0.984 IL6 10 ng/mL 0.5605 4.494 3.4060 - 5.9295 0.986 IL6 100 ng/mL 0.5772 4.4834 3.4583 - 5.8123 0.988 SCF 0.0 ng/ml 0.5433 5.0496 3.8776 - 6.5759 0.988 SCF 0.01 ng/mL 0.5206 5.1184 3.7436 - 6.9982 0.984 SCF 0.1 ng/mL 0.5289 4.7638 3.5384 - 6.4137 0.985 SCF 1 ng/mL 0.5263 4.9426 3.7637 - 6.4909 0.987 SCF 10 ng/mL 0.5293 4.9611 3.5256 - 6.9812 0.98 SCF 100 ng/mL 0.5473 4.8079 3.7504 - 6.1636 0.989 FLT3 0.0 ng/ml 0.5785 4.0982 2.9655 - 5.6635 0.982 FLT3 0.01 ng/mL 0.5549 3.251 2.3904 - 4.4215 0.984 FLT3 0.1 ng/mL 0.5837 4.0456 3.1306 - 5.2282 0.988 FLT3 1 ng/mL 0.5677 4.1235 2.9621 - 5.7402 0.981 FLT3 10 ng/mL 0.567 3.6648 2.7944 - 4.8065 0.987 FLT3 100 ng/mL 0.6116 3.9157 2.9477 - 5.2015 0.986 IL4 0.0 ng/ml 0.494 6.2811 4.3841 - 8.9990 0.979 IL4 0.01 ng/mL 0.4721 7.6786 5.1536 - 11.4406 0.974 IL4 0.1 ng/mL 0.4582 10.607 7.3974 - 15.2093 0.978 IL4 1 ng/mL 0.4529 11.2471 7.8367 - 16.1418 0.978 IL4 10 ng/mL 0.4687 10.4343 7.1849 - 15.1533 0.977 IL4 100 ng/mL 0.4579 11.1402 7.6311 - 16.2629 0.976 TSLP 0.0 ng/ml 0.5017 4.9482 3.5263 - 6.9434 0.981 TSLP 0.01 ng/mL 0.4805 5.692 3.8453 - 8.4256 0.975 TSLP 0.1 ng/mL 0.5043 8.314 6.0702 - 11.3872 0.983 TSLP 1 ng/mL 0.456 13.35 10.1901 - 17.4896 0.987 TSLP 10 ng/mL 0.4007 18.4296 12.8535 - 26.4247 0.978 TSLP 100 ng/mL 0.4177 17.6412 11.9235 - 26.1008 0.974 MCSF 0.0 ng/ml 0.5307 4.8682 3.5748 - 6.6296 0.984 MCSF 0.01 ng/mL 0.5375 4.803 3.0670 - 7.5216 0.968 MCSF 0.1 ng/mL 0.5247 5.4838 3.8284 - 7.8550 0.979 MCSF 1 ng/mL 0.5357 4.6983 3.2180 - 6.8595 0.977 MCSF 10 ng/mL 0.517 4.6896 3.2354 - 6.7975 0.978 MCSF 100 ng/mL 0.5489 4.943 3.4050 - 7.1756 0.978 IL9 0.0 ng/ml 0.5582 4.2149 2.9368 - 6.0491 0.979 IL9 0.01 ng/mL 0.5585 4.3679 3.0111 - 6.3359 0.977 IL9 0.1 ng/mL 0.5698 4.0533 2.8653 - 5.7341 0.98 IL9 1 ng/mL 0.538 4.6609 3.1394 - 6.9198 0.975 IL9 10 ng/mL 0.5789 4.4575 2.8883 - 6.8792 0.97 IL9 100 ng/mL 0.5306 5.3572 3.5917 - 7.9905 0.975 GMCSF 0.0 ng/ml 0.4922 4.9682 3.4753 - 7.1024 0.979 GMCSF 0.01 ng/mL 0.5195 4.4331 3.1515 - 6.2359 0.981 GMCSF 0.1 ng/mL 0.4903 5.2002 3.7301 - 7.2496 0.982 GMCSF 1 ng/mL 0.5287 5.0754 3.5354 - 7.2862 0.978 GMCSF 10 ng/mL 0.4985 5.1825 3.6136 - 7.4324 0.979 GMCSF 100 ng/mL 0.5077 5.2664 3.9156 - 7.0832 0.985 CXCL12 0.0 ng/ml 0.5302 4.2517 3.0049 - 6.0157 0.98 CXCL12 0.01 ng/mL 0.5506 4.02 2.8966 - 5.5790 0.982 CXCL12 0.1 ng/mL 0.555 4.3428 3.0724 - 6.1384 0.98 CXCL12 1 ng/mL 0.5543 4.9481 3.5552 - 6.8868 0.982 CXCL12 10 ng/mL 0.5257 6.341 4.6141 - 8.7143 0.983 CXCL12 100 ng/mL 0.5626 7.7776 5.4588 - 11.0814 0.979 GCSF 0.0 ng/ml 0.4859 5.3848 3.8070 - 7.6163 0.98 GCSF 0.01 ng/mL 0.4888 5.6829 4.1379 - 7.8048 0.983 GCSF 0.1 ng/mL 0.4995 5.2436 3.5467 - 7.7522 0.975 GCSF 1 ng/mL 0.5238 4.4557 2.9858 - 6.6491 0.974 GCSF 10 ng/mL 0.5082 5.5333 3.8070 - 8.0422 0.977 GCSF 100 ng/mL 0.5071 5.5916 3.8599 - 8.1003 0.978 TGFb 0.0 ng/ml 0.5196 4.4138 3.1588 - 6.1674 0.981 TGFb 0.01 ng/mL 0.8345 2.0792 1.3877 - 3.1152 0.972 TGFb 0.1 ng/mL 1.3386 1.0712 0.6824 - 1.6815 0.943 TGFb 1 ng/mL 1.1768 1.2921 0.8022 - 2.0810 0.949 TGFb 10 ng/mL 1.0645 1.4597 0.8969 - 2.3756 0.954 TGFb 100 ng/mL 1.258 1.4057 0.8535 - 2.3151 0.947 IL2 0.0 ng/ml 0.5186 4.3969 3.0447 - 6.3495 0.978 IL2 0.01 ng/mL 0.4837 4.8218 3.3902 - 6.8578 0.98 IL2 0.1 ng/mL 0.4856 4.531 3.0037 - 6.8346 0.974 IL2 1 ng/mL 0.51 4.4851 3.1998 - 6.2866 0.981 IL2 10 ng/mL 0.5181 4.753 3.2444 - 6.9630 0.977 IL2 100 ng/mL 0.507 4.6062 3.3039 - 6.4219 0.982 IL7 0.0 ng/ml 0.4659 7.0902 5.2763 - 9.5276 0.985 IL7 0.01 ng/mL 0.3318 61.9094 41.1312 - 93.1840 0.971 IL7 0.1 ng/mL 0.3661 251.4246 157.6730 - 400.9203 0.958 IL7 1 ng/mL 0.3761 281.2124 165.0664 - 479.0824 0.947 IL7 10 ng/mL 0.383 286.5185 173.4620 - 473.2615 0.95 IL7 100 ng/mL 0.352 448.189 245.0635 - 819.6787 0.938 sample regnumber supplier name supplier ID salt name salt eqs solvate name solvate eqs formula weight molsmiles synonym SJ000000250-8 SJ000000250 SIGMA P 9708 CHLORIDE 1 NO_SOLVATE 0 376.9439 CCCNC[C@H](O)COc1ccccc1C(=O)CCc2ccccc2 PROPAFENONE SJ000000854-6 SJ000000854 SIGMA Q 0125 NO_SALT 0 NO_SOLVATE 0 302.2357 OC1=C(Oc2cc(O)cc(O)c2C1=O)c3ccc(O)c(O)c3 QUERCETIN SJ000113084-4 SJ000113084 SIGMA D 9815 METHANESULFONATE 1 NO_SOLVATE 0 546.5751 COc1cc2nc(nc(N)c2cc1OC)N3CCN(CC3)C(=O)C4COc5ccccc5O4 DOXAZOSIN SJ000126662-3 SJ000126662 SIGMA 861669 NO_SALT 0 NO_SOLVATE 0 434.4264Nc1nc(SCc2ccc(cc2)[N+](=O)[O-])c3ncn([C@@H]4O[C@H](CO)[C@H](O)C4O)c3n1 NBTGR SJ000285182-2 SJ000285182 MICROSOURCE 1501107 NO_SALT 0 NO_SOLVATE 0CC(=C)[C@@H]1[C@H]2OC(=O)[C@@H]1[C@]3(O)C[C@H]4O[C@ 292.2839 ]45C(=O)O[C@H]2[C@]35CPICROTOXININ SJ000285183-2 SJ000285183 MICROSOURCE 1500169 CHLORIDE 1 NO_SOLVATE 0 340.0325 CCCCCCCCCCCCCCCC[n+]1ccccc1 CETYLPYRIDINIUM CHLORIDE SJ000285185-4 SJ000285185 PRESTWICK 548 PHOSPHATE 2 NO_SOLVATE 0 509 CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12 CHLOROQUINE DIPHOSPHATE SJ000285188-6 SJ000285188 SIGMA C 6645 CHLORIDE 1 NO_SOLVATE 0 278.7166 NC1=NC(=O)N(C=C1)[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O CYTARABINE SJ000285190-2 SJ000285190 MICROSOURCE 1500305 NO_SALT 0 NO_SOLVATE 0 130.0772 Oc1ncc(F)c(O)n1 FLUOROURACIL SJ000285193-1 SJ000285193 MICROSOURCE 1500375 NO_SALT 0 NO_SOLVATE 0 156.0535 CN(CCCl)CCCl CHLORMETHINE SJ000285194-2 SJ000285194 MICROSOURCE 1500382 NO_SALT 0 NO_SOLVATE 0 305.2002 N[C@@H](Cc1ccc(cc1)N(CCCl)CCCl)C(=O)O MELPHALAN SJ000285194-4 SJ000285194 SIGMA M 2011 NO_SALT 0 NO_SOLVATE 0 305.2002 NC(Cc1ccc(cc1)N(CCCl)CCCl)C(=O)O MELPHALAN SJ000285195-2 SJ000285195 MICROSOURCE 1500387 NO_SALT 0 NO_SOLVATE 0 152.177 Sc1[nH]cnc2ncnc12 MERCAPTOPURINE SJ000285196-2 SJ000285196 MICROSOURCE 1500398 NO_SALT 0 NO_SOLVATE 0 454.4392 CN(Cc1cnc2nc(N)nc(N)c2n1)c3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O METHOTREXATE SJ000285197-1 SJ000285197 MICROSOURCE 1500674 NO_SALT 0 NO_SOLVATE 0 320.3371 COc1c(C)c2COC(=O)c2c(O)c1C\C=C(/C)\CCC(=O)O MYCOPHENOLIC ACID SJ000285200-6 SJ000285200 SIGMA P 0547 2-HYDROXYETHANESULFONATE 2 NO_SOLVATE 0 590.4194 NC(=N)c1ccc(OCCCCCOc2ccc(cc2)C(=N)N)cc1 PENTAMIDINE ISETHIONATE SJ000285202-2 SJ000285202 MICROSOURCE 1500522 CHLORIDE 2 NO_SOLVATE 0 470.9568 CCN(CC)CCCC(C)Nc1c2ccc(Cl)cc2nc3ccc(OC)cc13 QUINACRINE SJ000285203-5 SJ000285203 SIGMA R 8875 NO_SALT 0 NO_SOLVATE 0 394.4171 COc1cc2OC[C@H]3Oc4c5C[C@@H](Oc5ccc4C(=O)[C@H]3c2cc1OC)C(=C)C ROTENONE SJ000285206-2 SJ000285206 MICROSOURCE 1500651 NO_SALT 0 NO_SOLVATE 0 334.4115 O=C1CC2OCC=C3CN4CC[C@@]56C4C[C@@H]3[C@@H]2C5N1c7ccccc67 STRYCHNINE SJ000285207-1 SJ000285207 MICROSOURCE 1500572 SODIUM(I) 1 NO_SOLVATE 0 405.8295 CC[Hg]Sc1ccccc1C(=O)O THIMEROSAL SJ000285208-3 SJ000285208 MICROSOURCE 1500573 NO_SALT 0 NO_SOLVATE 0 167.1917 Nc1nc(S)c2[nH]cnc2n1 THIOGUANINE SJ000285210-2 SJ000285210 MICROSOURCE 1500171 NO_SALT 0 NO_SOLVATE 0 304.2121 OC(=O)CCCc1ccc(cc1)N(CCCl)CCCl CHLORAMBUCIL SJ000285212-1 SJ000285212 MICROSOURCE 1501105 CHLORIDE 2 NO_SOLVATE 0COc1ccc(C[C@H](N)C(=O)N[C@@H]2[C@@H](CO)OC([C@@H]2O)n3cn 542.5095 c4c(ncnc34)N(C)C)cc1PUROMYCIN SJ000285215-1 SJ000285215 MICROSOURCE 1500272 CHLORIDE 2 NO_SOLVATE 0 551.6389CC[C@H]1CN2CCc3cc(OC)c(OC)cc3C2C[C@@H]1CC4NCCc5cc(OC)c(OC)cc45 EMETINE SJ000285215-6 SJ000285215 SIGMA E 2375 CHLORIDE 2 NO_SOLVATE 0 551.6389CC[C@H]1CN2CCc3cc(OC)c(OC)cc3[C@@H]2C[C@@H]1C[C@H]4NCCc5cc(OC)c(OC)cc45 EMETINE SJ000285218-5 SJ000285218 SIGMA C 7632 NO_SALT 0 NO_SOLVATE 0 196.1998 CC12C3CCC(O3)C1(C)C(=O)OC2=O CANTHARIDIN SJ000285219-2 SJ000285219 MICROSOURCE 1501189 NO_SALT 0 NO_SOLVATE 0 246.1924 C[C@H]1OC(C(O)[C@@H]1O)N2C=C(F)C(=O)NC2=O FLUORO-5'-DEOXYURIDINE SJ000285219-5 SJ000285219 SIGMA F 8791 NO_SALT 0 NO_SOLVATE 0 246.1924 C[C@H]1O[C@H]([C@H](O)[C@@H]1O)N2C=C(F)C(=O)NC2=O FLUORO-5'-DEOXYURIDINE SJ000285220-5 SJ000285220 SIGMA P 0667 NO_SALT 0 NO_SOLVATE 0 248.3175 C\C\1=C\CC[C@@]2(C)O[C@@H]2[C@H]3OC(=O)C(=C)[C@@H]3CC1 PARTHENOLIDE SJ000285221-4 SJ000285221 SIGMA A 1784 NO_SALT 0 NO_SOLVATE 0 440.4127 Nc1nc(N)c2nc(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)C(=O)O)cnc2n1 AMINOPTERIN SJ000285225-2 SJ000285225 MICROSOURCE 1502108 NO_SALT 0 NO_SOLVATE 0CCCCC[C@@H]1[C@@H](OC(=O)CC(C)C)[C@H](C)OC(=O)[C@@H 534.5986 ](NC(=O)c2cccc(NC=O)c2O)[C@@H](C)OC1=OANTIMYCIN A SJ000285226-6 SJ000285226 SIGMA A 2169 NO_SALT 0 NO_SOLVATE 0 267.2413 CC1=CN([C@H]2C[C@@H]([N-][N+]#N)[C@@H](CO)O2)C(=O)NC1=O ZIDOVUDINE SJ000285227-1 SJ000285227 MICROSOURCE 1502111 NO_SALT 0 NO_SOLVATE 0 244.2046 NC1=NC(=O)N(C=N1)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O AZACITIDINE SJ000285228-4 SJ000285228 PRESTWICK 790 NO_SALT 0 NO_SOLVATE 0 281.3474 C[C@H]1C[C@H](C)C(=O)[C@@H](C1)[C@H](O)CC2CC(=O)NC(=O)C2 CYCLOHEXIMIDE SJ000285229-2 SJ000285229 MICROSOURCE 1502113 NO_SALT 0 NO_SOLVATE 0 173.1267 NC(COC(=O)[CH-][N+]#N)C(=O)O AZASERINE SJ000285231-2 SJ000285231 MICROSOURCE 1502117 POTASSIUM(I) 2 NO_SOLVATECC(C)CC(=O)OC1C(O[C@@H]2C[C@H]([C@H]3CC[C@@]45CC(CC 0 802.9918 [C@H]4[C@]3(C)C2)C(=C)[C@@H]5O)C(=O)O)OC(CO)C(OS(=OATRACTYLOSIDE)(=O)[O-])C1OS(=O)(=O)[O-] SJ000285232-1 SJ000285232 MICROSOURCE 2300332 NO_SALT 0 NO_SOLVATE 0 414.4052COc1cc(cc(OC)c1OC)[C@H]2[C@@H]3[C@H](COC3=O)[C@@H](O)c4cc5OCOc5cc24 PODOFILOX SJ000285232-8 SJ000285232 SIGMA P 4405 NO_SALT 0 NO_SOLVATE 0 414.4052COc1cc(cc(OC)c1OC)[C@H]2[C@@H]3C(COC3=O)[C@@H](O)c4cc5OCOc5cc24 PODOFILOX SJ000285234-2 SJ000285234 MICROSOURCE 1503602 SODIUM(I) 1CC[C@H]([C@H]1CC[C@H](C)[C@@H](O1)[C@@H](C)[C@H](O) NO_SOLVATE 0 773.9986[C@H](C)C(=O)[C@H](CC)[C@H]2OC3(O[C@@]4(CC[C@](C)(O4)[C@H]5CC[C@](O)(CC)[C@H](C)O5)[C@H](O)C=C3)[C@H](SALINOMYCIN C)C[C@@H]2C)C(=O)O SJ000285235-3 SJ000285235 PRESTWICK 396 NO_SALT 0 NO_SOLVATECOc1cc(cc(OC)c1O)[C@H]2[C@@H]3[C@H](COC3=O)[C@H](O[C@@H]4 0 588.5565 O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]4O)c6cc7OCOc7cc26ETOPOSIDE SJ000285238-3 SJ000285238 MICROSOURCE 1500205 NO_SALT 0 NO_SOLVATE 0 399.437 COC1=CC=C2C(=CC1=O)[C@H](CCc3cc(OC)c(OC)c(OC)c23)NC(=O)C COLCHICINE SJ000285241-3 SJ000285241 MICROSOURCE 1500133 NO_SALT 0 NO_SOLVATE 0 277.2625 Cn1cnc(c1Sc2[nH]cnc3ncnc23)[N+](=O)[O-] AZATHIOPRINE SJ000285242-3 SJ000285242 MICROSOURCE 1500138 CHLORIDE 1 NO_SOLVATE 0 448.1273 CC(C)(C)CC(C)(C)c1ccc(OCCOCC[N+](C)(C)Cc2ccccc2)cc1 BENZETHONIUM CHLORIDE SJ000285243-2 SJ000285243 MICROSOURCE 330002 NO_SALT 0 NO_SOLVATE 0 334.3272CO[C@@]12[C@@H]3NC3CN1C4=C([C@@H]2COC(=O)N)C(=O)C(=C(C)C4=O)N MITOMYCIN SJ000285244-3 SJ000285244 MICROSOURCE 1500319 NO_SALT 0 NO_SOLVATECC(C)CC1NC(=O)C(CCCN)NC(=O)C(NC(=O)C2CCCN2C(=O)C(Cc3 0 1141.4468 ccccc3)NC(=O)C(CC(C)C)NC(=O)C(CCCN)NC(=O)C(NC(=O)C4CCCN4GRAMICIDINC(=O)C(Cc5ccccc5)NC1=O)C(C)C)C(C)C SJ000285246-2 SJ000285246 MICROSOURCE 1500618 CHLORIDE 1 NO_SOLVATE 0 259.7805 C[n+]1c2cc(N)ccc2cc3ccc(N)cc13 ACRIFLAVINIUM SJ000285249-1 SJ000285249 MICROSOURCE 330001 NO_SALT 0CC(C)C1NC(=O)C(NC(=O)C2=C(N)C(=O)C(=C3Oc4c(C)ccc(C(=O)NC NO_SOLVATE 0 1253.44095C(C)OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C6CCCC6C(=O)C(NC5=O)C(C)C)c4N=C23)C)C(C)OC(=O)C(C(C)C)N(C)C(=O)CNDACTINOMYCIN (C)C(=O)C7CCCC7C1=O SJ000285256-3 SJ000285256 MICROSOURCE 200022 CHLORIDE 1 NO_SOLVATE 0CC[C@@]1(O)C[C@H](O[C@H]2C[C@@H]([C@H](O)[C@H](C)O2 605.0996 )N(C)C)c3c(O)c4C(=O)c5c(O)cccc5C(=O)c4cc3[C@H]1C(=O)OCAKLAVINE HYDROCHLORIDE SJ000285261-3 SJ000285261 MICROSOURCE 1500315 CHLORIDE 1 NO_SOLVATE 0 408.0252 CN(C)c1ccc(cc1)C(=C2C=CC(=[N+](C)C)C=C2)c3ccc(cc3)N(C)C GENTIAN VIOLET SJ000285262-1 SJ000285262 MICROSOURCE 1500122 NO_SALT 0C[C@@H]1OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)C[C@]2(O)C[C NO_SOLVATE 0 924.079 @H](O)C(C(C[C@@H](OC3OC(C)C(O)[C@@H](N)C3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\[C@H](C)[C@@H](O)[C@H]1C)O2)C(AMPHOTERICIN B =O)O SJ000285263-2 SJ000285263 MICROSOURCE 1500324 NO_SALT 0 NO_SOLVATE 0 270.0899 OC(=O)c1ccc(cc1)S(=O)(=O)N(Cl)Cl HALAZONE SJ000285267-3 SJ000285267 MICROSOURCE 1503322 NO_SALT 0 NO_SOLVATE 0 240.4328 CN(C)C(=S)SSC(=S)N(C)C THIRAM SJ000285270-2 SJ000285270 MICROSOURCE 1503324 NO_SALT 0 NO_SOLVATE 0 189.2183 S=P(N1CC1)(N2CC2)N3CC3 THIOTEPA SJ000285272-2 SJ000285272 MICROSOURCE 1503059 NO_SALT 0 NO_SOLVATE 0 246.1924 OC[C@H]1OC(C[C@H]1O)N2C=C(F)C(=O)NC2=O FLOXURIDINE SJ000285273-3 SJ000285273 MICROSOURCE 1500328 NO_SALT 0 NO_SOLVATE 0 406.9035 Oc1c(Cl)cc(Cl)c(Cl)c1Cc2c(O)c(Cl)cc(Cl)c2Cl HEXACHLOROPHENE SJ000285276-2 SJ000285276 MICROSOURCE 1503239 NO_SALT 0 NO_SOLVATE 0 356.4817 CCN(CC)CCNc1ccc(CO)c2Sc3ccccc3C(=O)c12 HYCANTHONE SJ000285278-1 SJ000285278 MICROSOURCE 1503266 NO_SALT 0 NO_SOLVATE 0 301.3204 COC(=O)Nc1nc2cc(ccc2[nH]1)C(=O)c3cccs3 NOCODAZOLE SJ000285279-2 SJ000285279 MICROSOURCE 2300219 CHLORIDE 1 NO_SOLVATE 0 201.7395 CC[N+](C)(C)c1cccc(O)c1 EDROPHONIUM SJ000285285-3 SJ000285285 MICROSOURCE 1503065 NO_SALT 0 NO_SOLVATE 0 210.2794 CN(C)c1nc(nc(n1)N(C)C)N(C)C ALTRETAMINE SJ000285292-10 SJ000285292 SIGMA C 3909 NO_SALT 0 NO_SOLVATE 0 102.0919 N[C@@H]1CONC1=O CYCLOSERINE SJ000285294-1 SJ000285294 MICROSOURCE 1500644 NO_SALT 0 NO_SOLVATE 0 336.7379 CC(=O)O[Hg]c1ccccc1 PHENYLMERCURIC ACETATE SJ000285299-2 SJ000285299 MICROSOURCE 1503214 NO_SALT 0 NO_SOLVATE 0 256.2551 CCC1=CN(C2OCC(O)C2CO)C(=O)NC1=O EDOXUDINE SJ000285307-3 SJ000285307 MICROSOURCE 1503244 SODIUM(I) 1 NO_SOLVATE 0CC[C@H](C1OC(CC)(C[C@@H]1C)C2CC[C@](O)(CC)[C@H](C)O 613.7877 2)C(=O)C(C)[C@@H](O)[C@H](C)CCc3ccc(C)c(O)c3C(=O)OLASALOCID SODIUM SJ000285308-1 SJ000285308 MICROSOURCE 1503127 CHLORIDE 2 NO_SOLVATE 0 527.6643 Cc1cc(N)c2ccccc2[n+]1CCCCCCCCCC[n+]3c(C)cc(N)c4ccccc34 DEQUALINIUM CHLORIDE SJ000285313-3 SJ000285313 MICROSOURCE 1505337 NO_SALT 0 NO_SOLVATE 0 434.6126 CCCCCCCC\C=C\CCCCCCCCOP(=O)(O)OCC[N+](C)(C)C ELAIDYLPHOSPHOCHOLINE SJ000285315-2 SJ000285315 MICROSOURCE 1505317 NO_SALT 0 NO_SOLVATE 0 257.2614 CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O CARMOFUR SJ000285316-4 SJ000285316 PRESTWICK 302 CHLORIDE 1 NO_SOLVATE 0CCC[C@@H]1C[C@H](N(C)C1)C(=O)N[C@H]([C@@H](C)O)[C@H 442.0373 ]2O[C@H](SC)[C@H](O)[C@@H](O)[C@@H]2OLINCOMYCIN SJ000285317-2 SJ000285317 MICROSOURCE 1500456 NO_SALT 0 NO_SOLVATE 0 145.1579 Oc1cccc2cccnc12 OXYQUINOLINE SJ000285318-7 SJ000285318 SIGMA E 8375 NO_SALT 0 NO_SOLVATE 0 275.3461 CNC(=O)Oc1ccc2N(C)[C@H]3N(C)CC[C@@]3(C)c2c1 PHYSOSTIGMINE SALICYLATE SJ000285319-1 SJ000285319 MICROSOURCE 1503074 CHLORIDE 2 NO_SOLVATE 0 579.7898 CCCCC(CC)CN=C(N)N=C(N)NCCCCCCNC(=NC(=NCC(CC)CCCC)N)N ALEXIDINE HYDROCHLORIDE SJ000285321-4 SJ000285321 PRESTWICK 385 CHLORIDE 2 NO_SOLVATE 0 515.4809 OCCNCCNc1ccc(NCCNCCO)c2C(=O)c3c(O)ccc(O)c3C(=O)c12 MITOXANTRONE SJ000285323-3 SJ000285323 MICROSOURCE 1500637 SODIUM(I) 2 NO_SOLVATE 0 752.6878 O[Hg]c1c(O)c(Br)cc2C(=C3C=C(Br)C(=O)C=C3Oc12)c4ccccc4C(=O)O MERBROMIN SJ000285327-1 SJ000285327 MICROSOURCE 310035 SULFATE 1 NO_SOLVATE 0 428.4289 C[n+]1cc2c3OCOc3ccc2c4ccc5cc6OCOc6cc5c14 SANGUINARINE SULFATE SJ000285332-1 SJ000285332 MICROSOURCE 1500260 NO_SALT 0 NO_SOLVATE 0 318.7101 S=C1CC=CC=[N+]1O[Zn]ON2C=CC=CC2=S PYRITHIONE ZINC SJ000285334-4 SJ000285334 PRESTWICK 152 PHOSPHATE 1CO[C@H]1C[C@H](O[C@H]2[C@H](C)[C@@H](O[C@@H]3O[C@H] NO_SOLVATE 0 782.8583(C)C[C@@H]([C@H]3O)N(C)C)[C@@H](C)C[C@@]4(CO4)C(=O)[C@H](C)[C@@H](O)[C@@H](C)[C@@H](C)OC(=O)[C@@H]2C)OOLEANDOMYCIN PHOSPHATE [C@@H](C)[C@@H]1O SJ000285335-1 SJ000285335 MICROSOURCE 1500611 SULFATE 1 NO_SOLVATECC[C@]1(O)CC2CN(CCc3c([nH]c4ccccc34)[C@@](C2)(C(=O)OC)c5cc6c(cc5O 0 907.0741 C)N(C)[C@H]7[C@](O)([C@H](OC(=O)C)[C@]8(CC)C=CCN9CCVINBLASTINE[C@]67[C@H]89)C(=O)OC)C1 SJ000285335-4 SJ000285335 SIGMA V 1377 SULFATE 1 NO_SOLVATE CCC1(O)CC2CN(CCc3c([nH]c4ccccc34)[C@@](C2)(C(=O)OC)c5cc6c(cc5OC)N0 907.0741 (C)C7[C@](O)([C@H](OC(=O)C)[C@]8(CC)C=CCN9CC[C@]67[VINBLASTINE C@H]89)C(=O)OC)C1 SJ000285337-5 SJ000285337 PRESTWICK 256 NO_SALT 0 NO_SOLVATE 0 300.4351 C\C(=C\C(=O)O)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C ISOTRETINOIN SJ000285337-8 SJ000285337 SIGMA R 2625 NO_SALT 0 NO_SOLVATE 0 300.4351 C\C(=C/C=C/C(=C/C(=O)O)/C)\C=C\C1=C(C)CCCC1(C)C TRETINOIN SJ000285338-3 SJ000285338 PRESTWICK 143 NO_SALT 0 NO_SOLVATE 0 505.4466 Clc1ccc(NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)Nc2ccc(Cl)cc2)cc1 CHLORHEXIDINE SJ000285343-2 SJ000285343 MICROSOURCE 1502025 NO_SALT 0 NO_SOLVATE 0 355.3894 OC(=O)CCC(=O)Nc1ccc(cc1)S(=O)(=O)Nc2nccs2 SUCCINYLSULFATHIAZOLE SJ000285358-5 SJ000285358 SIGMA H 4001 NO_SALT 0 NO_SOLVATE 0C[C@]12CCC(=O)C=C1CC[C@H]3[C@@H]4CC[C@](O)(C(=O)CO) 362.4599 [C@@]4(C)C[C@H](O)[C@H]23HYDROCORTISONE SJ000285363-5 SJ000285363 SIGMA M-149 METHANESULFONATE 1 NO_SOLVATE 0 451.6479 CSc1ccc2Sc3ccccc3CC(N4CCN(C)CC4)c2c1 METITEPINE SJ000285364-2 SJ000285364 PRESTWICK 134 CHLORIDE 1 NO_SOLVATE 0 450.0178 COc1ccc(cc1)[C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)C DILTIAZEM SJ000285365-1 SJ000285365 MICROSOURCE 1502258 SODIUM(I) 1 NO_SOLVATECC[C@]1(O)OC([C@@H](C)C[C@H]1C)[C@H]2C[C@H](C)C(O2) 0 691.898 [C@]3(CC)CC[C@@H](O3)[C@]4(C)CCC5(C[C@H](O)[C@@H](C)[C@H](O5)[C@H](C)[C@@H](OC)[C@H](C)C(=O)O)O4MONENSIN SODIUM SALT SJ000285368-3 SJ000285368 PRESTWICK 710 NO_SALT 0 NO_SOLVATE 0C[C@]12CC[C@H]3[C@@H](CC[C@]4(O)C[C@@H](O)CC[C@]34C 404.4965 =O)[C@@]1(O)CC[C@@H]2C5=CC(=O)OC5STROPHANTHIDIN SJ000285369-1 SJ000285369 MICROSOURCE 210515 NO_SALT 0 NO_SOLVATE 0 204.1788 OC1=CC=Cc2ccc(O)c(O)c2C1=O PYROGALLIN SJ000285373-9 SJ000285373 SIGMA A 0257 SULFATE 0.5 NO_SOLVATE 0 337.4194 CN1C2CCC1CC(C2)OC(=O)C(CO)c3ccccc3 ATROPINE SJ000285375-2 SJ000285375 MICROSOURCE 1504174 CHLORIDE 1 NO_SOLVATE 0 275.2411 CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1 BUPROPION SJ000285382-3 SJ000285382 PRESTWICK 730 NO_SALT 0 NO_SOLVATEC[C@@H]1CC[C@@]2(OC1)O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C 0 430.6199 [C@@H](O)CC[C@]6(C)[C@H]5CC(=O)[C@]4(C)[C@H]3[C@@H]HECOGENIN 2C SJ000285383-1 SJ000285383 MICROSOURCE 1501114 FUMARATE 1 NO_SOLVATE 0 407.5258 CN1CCC(=C2c3ccccc3Sc4ccccc24)CC1 PIMETHIXENE MALEATE SJ000285387-8 SJ000285387 SIGMA E 3250 SULFATE 0.5 NO_SOLVATE 0 213.2822 CN[C@@H](C)[C@H](O)c1ccccc1 PSEUDOEPHEDRINE HYDROCHLORIDE SJ000285396-2 SJ000285396 MICROSOURCE 1502162 NO_SALT 0 NO_SOLVATE 0 199.6342 NC(Cc1ccc(Cl)cc1)C(=O)O CHLOROPHENYLALANINE SJ000285400-2 SJ000285400 MICROSOURCE 310010 NO_SALT 0 NO_SOLVATE 0 232.3181 C[C@H]1CCC[C@]2(C)C[C@H]3OC(=O)C(=C)[C@H]3C=C12 HELENINE SJ000285410-5 SJ000285410 SIGMA C 9911 NO_SALT 0 NO_SOLVATE 0 348.352 CC[C@@]1(O)C(=O)OCC2=C1C=C3N(Cc4cc5ccccc5nc34)C2=O CAMPTOTHECIN SJ000285413-1 SJ000285413 MICROSOURCE 1505235 NO_SALT 0 NO_SOLVATE 0 324.4549 CC(=O)OCC(O)CC(=O)CCCCCCCCCCCC#C AVOCADYNONE ACETATE SJ000285423-2 SJ000285423 MICROSOURCE 1504181 NO_SALT 0 NO_SOLVATE 0COC(=O)[C@]1(C)CC[C@]2(C)CC[C@]3(C)C4=CC=C5C(=C(O)C 464.6362 (=O)C=C5[C@]4(C)CC[C@@]3(C)[C@@H]2C1)CPRISTIMERIN SJ000285426-2 SJ000285426 MICROSOURCE 1502177 ACETATE 1 NO_SOLVATE 0 468.5428 CSCCC(N)C(=O)NC(CC(C)C)C(=O)NC(Cc1ccccc1)C(=O)OMETHIONYL-LEUCYLPHENYLALANINE ACETATE SJ000285431-2 SJ000285431 MICROSOURCE 310028 NO_SALT 0 NO_SOLVATE 0COC1=CC(C)[C@@H]2C[C@H]3OC(=O)C[C@H]4C(=C(OC)C(=O)C 388.4541 ([C@@]34C)[C@@]2(C)C1=O)CQUASSIN SJ000285433-1 SJ000285433 MICROSOURCE 1505230 NO_SALT 0 NO_SOLVATE 0 369.4606 O=C1CCc2cc(OCCCCc3nnnn3C4CCCCC4)ccc2N1 CILOSTAZOL SJ000285436-3 SJ000285436 PRESTWICK 498 NO_SALT 0 NO_SOLVATE 0 282.3321C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@@]23OO4ARTEMISININ SJ000285439-2 SJ000285439 MICROSOURCE 1500603 NO_SALT 0CC(C)CC1NC(=O)C(CCCN)NC(=O)C(NC(=O)C(Cc2ccc(O)cc2)NC(=O)C NO_SOLVATE 0 1272.4458 (CCC(=O)O)NC(=O)C(CC(=O)O)NC(=O)C(Cc3ccccc3)NC(=O)C(Cc4ccccc4)NTYROTHRICINC(=O)C5CCCN5C(=O)C(Cc6ccccc6)NC1=O)C(C)C SJ000285440-2 SJ000285440 MICROSOURCE 1504240 NO_SALT 0 NO_SOLVATE 0 158.1534 O=C1C=CC(=O)c2ccccc12 1,4-NAPHTHOQUINONE SJ000285442-1 SJ000285442 MICROSOURCE 1505345 NO_SALT 0 NO_SOLVATE 0 368.3799 COc1cc(\C=C\C(=CC(=O)\C=C\c2ccc(O)c(OC)c2)O)ccc1O CURCUMIN SJ000285443-2 SJ000285443 MICROSOURCE 1500762 NO_SALT 0 NO_SOLVATE 0 290.3126 Oc1ccc(cc1)C(=C2C=CC(=O)C=C2)c3ccc(O)cc3 ROSOLIC ACID SJ000285445-2 SJ000285445 MICROSOURCE 1500775 NO_SALT 0 NO_SOLVATE 0 747.8288 OC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1 TETRAC SJ000285450-2 SJ000285450 MICROSOURCE 1500810 NO_SALT 0 NO_SOLVATE 0 194.2319 Nc1c2ccccc2nc3ccccc13 9-AMINOACRIDINE SJ000285451-3 SJ000285451 PRESTWICK 586 CHLORIDE 1 NO_SOLVATE 0 371.8606 COc1ccc2cc3c4cc5OCOc5cc4CC[n+]3cc2c1OC BERBERINE CHLORIDE SJ000285452-1 SJ000285452 MICROSOURCE 1500813 NO_SALT 0 NO_SOLVATE 0CCCC1O[C@@H]2CC3C4CCC5=CC(=O)C=CC5(C)C4[C@@H](O)CC3 430.5338 (C)[C@@]2(O1)C(=O)COBUDESONIDE SJ000285452-5 SJ000285452 SIGMA B 7777 NO_SALT 0 NO_SOLVATE 0CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C 430.5338 @H]4[C@@H](O)C[C@]3(C)[C@@]2(O1)C(=O)COBUDESONIDE SJ000285453-3 SJ000285453 PRESTWICK 148 POTASSIUM(I) 1 NO_SOLVATE 0C[C@]12CCC(=O)C=C1C=C[C@@H]3[C@@H]2CC[C@@]4(C)[C@H] 397.5712 3CC[C@@]4(O)CCC(=O)OPOTASSIUM CANRENOATE SJ000285454-2 SJ000285454 MICROSOURCE 1500836 SODIUM(I) 1 NO_SOLVATE 0 438.4182 CC(=O)OCC1=C(N2C(SC1)[C@H](NC(=O)CCCC(N)C(=O)O)C2=O)C(=O)O CEPHALOSPORIN C SODIUM SJ000285460-1 SJ000285460 MICROSOURCE 1502030 NO_SALT 0 NO_SOLVATE 0 261.2301 CCN1C=C(C(=O)O)C(=O)c2cc3OCOc3cc12 OXOLINIC ACID SJ000285461-1 SJ000285461 MICROSOURCE 1501117 CHLORIDE 1 NO_SOLVATE 0 465.0491 CCN(CCCCOC(=O)c1ccc(OC)c(OC)c1)C(C)Cc2ccc(OC)cc2 MEBEVERINE HYDROCHLORIDE SJ000285462-2 SJ000285462 MICROSOURCE 1501118 2-HYDROXY-5-SULFONATOBENZOATE 1 NO_SOLVATE 0CN(C)[C@H]1[C@@H]2[C@@H](O)[C@@H]3C(=C)c4c(Cl)ccc(O)c4C(= 693.0637 C3C(=O)[C@]2(O)C(=C(C(=O)N)C1=O)O)OMECLOCYCLINE SULFOSALICYLATE SJ000285465-2 SJ000285465 MICROSOURCE 1501121 CHLORIDE 1 NO_SOLVATE 0 214.8018 CC12CC3CC(C)(C1)CC(N)(C3)C2 MEMANTINE SJ000285466-4 SJ000285466 SIGMA A 4147 SODIUM(I) 1 NO_SOLVATE 0 161.166 NCCCS(=O)(=O)[O-] HOMOTAURINE SJ000285484-2 SJ000285484 MICROSOURCE 1500639 CHLORIDE 1 NO_SOLVATE 0 188.6784 NCC(O)c1ccc(O)cc1 OCTOPAMINE HYDROCHLORIDE SJ000285487-3 SJ000285487 PRESTWICK 874 NO_SALT 0 NO_SOLVATE 0 180.164 CN1C(=O)NC(=O)c2c1ncn2C THEOBROMINE SJ000285490-1 SJ000285490 MICROSOURCE 201524 NO_SALT 0 NO_SOLVATE 0CC(=CCCC1(C)Oc2c(CC=C(C)C)c3OC45C6CC(C=C4C(=O)c3c(O)c2C=C 630.767 1)C(O)C5(C\C=C(\C)/C(=O)O)OC6(C)C)CDIHYDROGAMBOGIC ACID SJ000285502-5 SJ000285502 SIGMA A 8423 CHLORIDE 1 NO_SOLVATE 0 680.8116 CCCCc1oc2ccccc2c1C(=O)c3cc(I)c(OCCN(CC)CC)c(I)c3 AMIODARONE SJ000285504-2 SJ000285504 MICROSOURCE 1503270 CHLORIDE 1 NO_SOLVATE 0 255.8107 CCCNC(C)C(=O)Nc1ccccc1C PRILOCAINE SJ000285506-2 SJ000285506 MICROSOURCE 2300009 NO_SALT 0 NO_SOLVATE 0 410.549 CCN(CC)CCOc1ccc2c(c1)C(=O)c3cc(OCCN(CC)CC)ccc23 TILORONE SJ000285508-1 SJ000285508 MICROSOURCE 1503908 NO_SALT 0 NO_CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](O)C[C@H]3OC[C@@]3(SOLVATE 0 853.9061 OC(=O)C)C2[C@H](OC(=O)c4ccccc4)[C@]5(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c6ccccc6)c7ccccc7)C(=C1C5(C)C)CPACLITAXEL SJ000285512-1 SJ000285512 MICROSOURCE 300037 NO_SALT 0 NO_SOLVATE 0 376.4864 CC(=O)OC1C\C(=C\CC\C(=C\CC[C@](C)(O)C2CC1C(=C)C(=O)O2)\C)\C CRASSIN ACETATE SJ000285522-3 SJ000285522 MICROSOURCE 2300253 NO_SALT 0 NO_SOLVATE 0 151.2056 C[C@@H](N)[C@@H](O)c1ccccc1 EPHEDRINE SJ000285526-3 SJ000285526 PRESTWICK 950 NO_SALT 0 NO_SOLVATE 0 129.157 OC(=O)C1CCCNC1 NIPECOTIC ACID SJ000285536-1 SJ000285536 MICROSOURCE 1500487 NITRATE 1 NO_SOLVATE 0 270.2569 CC[C@H]1[C@@H](Cc2cncn2C)COC1=O PILOCARPINE SJ000285540-4 SJ000285540 SIGMA P 7791 CHLORIDE 1 NO_SOLVATE 0 418.9011 COc1cc2nc(nc(N)c2cc1OC)N3CCN(CC3)C(=O)c4occc4 PRAZOSIN SJ000285541-3 SJ000285541 PRESTWICK 274 NO_SALT 0 NO_SOLVATE 0C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@]34C) 360.444 [C@@H]1CC[C@]2(O)C(=O)COPREDNISOLONE SJ000285542-2 SJ000285542 MICROSOURCE 1500497 NO_SALT 0 NO_SOLVATE 0 402.4807CC(=O)OCC(=O)[C@@]1(O)CCC2C3CCC4=CC(=O)C=CC4(C)C3[C@@H](O)C[C@]12CPREDNISOLONE ACETATE SJ000285543-1 SJ000285543 MICROSOURCE 1500499 NO_SALT 0 NO_SOLVATE 0 358.4281 C[C@]12CC(=O)C3C(CCC4=CC(=O)C=C[C@]34C)C1CC[C@]2(O)C(=O)CO PREDNISONE SJ000285544-3 SJ000285544 PRESTWICK 476 PHOSPHATE 2 NO_SOLVATE 0 449.3467 COc1cc(NC(C)CCCN)c2ncccc2c1 PRIMAQUINE SJ000285547-5 SJ000285547 SIGMA P 9391 CHLORIDE 1 NO_SOLVATE 0 270.8253 CCN(CC)CCNC(=O)c1ccc(N)cc1 PROCAINAMIDE SJ000285549-5 SJ000285549 SIGMA P 9178 FUMARATE 2 NO_SOLVATE 0 602.1426 CN1CCN(CCCN2c3ccccc3Sc4ccc(Cl)cc24)CC1 PROCHLORPERAZINE SJ000285551-2 SJ000285551 MICROSOURCE 1500508 NO_SALT 0 NO_SOLVATE 0 314.4617 CC(=O)[C@H]1CCC2C3CCC4=CC(=O)CC[C@]4(C)C3CC[C@]12C PROGESTERONE SJ000285554-2 SJ000285554 MICROSOURCE 201580 NO_SALT 0 NO_SOLVATE 0 420.4544 CC(=CCc1c(O)c2C(=O)C(=COc2c3C=CC(C)(C)Oc13)c4ccc(O)c(O)c4)C POMIFERIN SJ000285564-2 SJ000285564 MICROSOURCE 1500476 SULFATE 1 NO_SOLVATE 0 232.2942 NNCCc1ccccc1 PHENELZINE SJ000285569-2 SJ000285569 MICROSOURCE 1500490 NO_SALT 0 NO_SOLVATE 0 86.1356 C1CNCCN1 PIPERAZINE SJ000285572-3 SJ000285572 MICROSOURCE 1500523 GLUCONATE 1 NO_SOLVATE 0 519.6167 COc1ccc2nccc([C@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4C=C)c2c1 QUININE SULFATE SJ000285572-4 SJ000285572 PRESTWICK 280 CHLORIDE 1 H2O 1 377 COc1ccc2nccc([C@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4C=C)c2c1 QUININE SULFATE SJ000285574-1 SJ000285574 MICROSOURCE 1500531 NO_SALT 0 NO_SOLVATE 0 124.1372 OCc1ccccc1O SALICYL ALCOHOL SJ000285577-2 SJ000285577 MICROSOURCE 1500539 NO_SALT 0 NO_SOLVATE 0CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]3CC[C@@]4(C) 416.5734 [C@@H](CC[C@@]45CCC(=O)O5)C13SPIRONOLACTONE SJ000285584-1 SJ000285584 MICROSOURCE 1500759 NO_SALT 0 NO_SOLVATE 0 272.2097 Oc1ccc2C(=O)c3c(O)ccc(O)c3C(=O)c2c1O QUINALIZARIN SJ000285586-2 SJ000285586 MICROSOURCE 107108 NO_SALT 0 NO_SOLVATE 0 288.4244 C[C@]12CCC(=O)C[C@@H]1CCC3C2CC[C@@]4(C)C3CCC4=O 5-ALPHA-ANDROSTAN-3,17-DIONE SJ000285587-1 SJ000285587 MICROSOURCE 200007 NO_SALT 0 NO_SOLVATE 0CC(=CCCC1(C)Oc2c(CC=C(C)C)c3OC45C6CC(C=C4C(=O)c3c(O)c2C=C 628.7511 1)C(=O)C5(C\C=C(\C)/C(=O)O)OC6(C)C)CGAMBOGIC ACID SJ000285588-1 SJ000285588 MICROSOURCE 200789 NO_SALT 0 NO_SOLVATE 0 254.2375 Oc1ccc(cc1)C2=COc3cc(O)ccc3C2=O DAIDZEIN SJ000285591-1 SJ000285591 MICROSOURCE 1500455 NO_SALT 0 NO_SOLVATE 0 324.3737 CCCCC1C(=O)N(N(C1=O)c2ccc(O)cc2)c3ccccc3 OXYPHENBUTAZONE SJ000285592-5 SJ000285592 SIGMA T 9262 CITRATE 1 NO_SOLVATE 0 560.6145 CC\C(=C(/c1ccccc1)\c2ccc(OCCN(C)C)cc2)\c3ccccc3 TAMOXIFEN SJ000285606-5 SJ000285606 SIGMA T 7508 CHLORIDE 1 NO_SOLVATE 0 299.8632 CCCCNc1ccc(cc1)C(=O)OCCN(C)C TETRACAINE HYDROCHLORIDE SJ000285608-2 SJ000285608 MICROSOURCE 1500576 NO_SALT 0 NO_SOLVATE 0 443.6252 CN(C)S(=O)(=O)c1ccc2Sc3ccccc3\C(=C/CCN4CCN(C)CC4)\c2c1 THIOTHIXENE SJ000285608-4 SJ000285608 SIGMA T 0780 CHLORIDE 1 NO_SOLVATE 0 479.1252 CN(C)S(=O)(=O)c1ccc2Sc3ccccc3\C(=C\CCN4CCN(C)CC4)\c2c1 THIOTHIXENE SJ000285610-5 SJ000285610 SIGMA T 9025 CHLORIDE 1 NO_SOLVATE 0 406.0745 CSc1ccc2Sc3ccccc3N(CCC4CCCCN4C)c2c1 THIORIDAZINE SJ000285614-1 SJ000285614 MICROSOURCE 1500582 SODIUM(I) 1 NO_SOLVATE 0 280.2845 Cc1ccc(cc1)C(=O)c2ccc(CC(=O)O)n2C TOLMETIN SJ000285618-1 SJ000285618 MICROSOURCE 1500615 NO_SALT 0 NO_SOLVATE 0 291.7295 Cc1cc(CC(=O)O)n(C)c1C(=O)c2ccc(Cl)cc2 ZOMEPIRAC SODIUM SJ000285619-2 SJ000285619 MICROSOURCE 1500621 NO_SALT 0 NO_SOLVATE 0 203.2404 CN1N(C(=O)C(=C1C)N)c2ccccc2 AMINOPHENAZONE SJ000285625-5 SJ000285625 PRESTWICK 577 CHLORIDE 1 NO_SOLVATE 0 389.9427COC(=O)[C@@H]1[C@@H](O)CC[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@H]3C[C@H]12YOHIMBINE HYDROCHLORIDE SJ000285630-6 SJ000285630 SIGMA I-106 NO_SALT 0 NO_SOLVATE 0 206.2808 CC(C)Cc1ccc(cc1)[C@H](C)C(=O)O IBUPROFEN SJ000285635-2 SJ000285635 MICROSOURCE 1500354 BROMIDE 1 NO_SOLVATE 0 412.3565 CC(C)[N+]1(C)[C@@H]2CCC1C[C@@H](C2)OC(=O)C(CO)c3ccccc3 IPRATROPIUM SJ000285638-1 SJ000285638 MICROSOURCE 1500359 CHLORIDE 1 NO_SOLVATE 0 336.8801 C[C@H](COc1ccccc1)N[C@H](C)[C@H](O)c2ccc(O)cc2 ISOXSUPRINE HYDROCHLORIDE SJ000285643-1 SJ000285643 MICROSOURCE 1500376 CHLORIDE 2 NO_SOLVATE 0 461.9482 Cc1cccc(CN2CCN(CC2)C(c3ccccc3)c4ccc(Cl)cc4)c1 MECLOZINE SJ000285646-1 SJ000285646 MICROSOURCE 1500380 NO_SALT 0 NO_SOLVATE 0 344.4876C[C@H]1CC2C3CC[C@H](C(=O)C)[C@@]3(C)C[C@H](O)C2[C@@]4(C)CCC(=O)C=C14 MEDRYSONE SJ000285651-2 SJ000285651 MICROSOURCE 1500396 NO_SALT 0 NO_SOLVATE 0 114.1688 Cn1ccnc1S THIAMAZOLE SJ000285652-2 SJ000285652 MICROSOURCE 1500397 NO_SALT 0 NO_SOLVATE 0 241.2405 COc1ccccc1OCC(O)COC(=O)N METHOCARBAMOL SJ000285655-1 SJ000285655 MICROSOURCE 1500403 NO_SALT 0 NO_SOLVATE 0 211.2145 C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O METHYLDOPA SJ000285657-1 SJ000285657 MICROSOURCE 1500406 NO_SALT 0 NO_SOLVATE 0C[C@H]1CC2C3CC[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)C2[ 374.4706 C@@]4(C)C=CC(=O)C=C14METHYLPREDNISOLONE SJ000285659-2 SJ000285659 MICROSOURCE 1500414 CHLORIDE 1 NO_SOLVATE 0CN(C)[C@H]1[C@@H]2C[C@@H]3Cc4c(ccc(O)c4C(=C3C(=O)[C@]2(O) 492.9 C(=C(C(=O)N)C1=O)O)O)N(C)CMINOCYCLINE SJ000285664-3 SJ000285664 PRESTWICK 46 CHLORIDE 1 NO_SOLVATE 0 245.7743 C(C1=NCCN1)c2cccc3ccccc23 NAPHAZOLINE SJ000285666-5 SJ000285666 SIGMA N 7634 NO_SALT 0 NO_SOLVATE 0 346.3346 COC(=C1C(C(=C(C)N=C1C)C(=O)OC)c2ccccc2[N+](=O)[O-])O NIFEDIPINE SJ000285667-2 SJ000285667 MICROSOURCE 1500433 NO_SALT 0 NO_SOLVATE 0 238.157 [O-][N+](=O)c1oc(\C=N\N2CC(=O)NC2=O)cc1 NITROFURANTOIN SJ000285668-3 SJ000285668 PRESTWICK 563 NO_SALT 0 NO_SOLVATE 0 413.4205 COc1ccc2[C@H](OC(=O)c2c1OC)[C@@H]3N(C)CCc4cc5OCOc5c(OC)c34NOSCAPINE HYDROCHLORIDE SJ000285671-2 SJ000285671 MICROSOURCE 1500438 NO_SALT 0 NO_SOLVATE 0 340.4559 CC(=O)O[C@]1(CCC2C3CCC4=CC(=O)CC[C@@H]4C3CC[C@]12C)C#C NORETHISTERONE ACETATE SJ000285674-3 SJ000285674 PRESTWICK 773 NO_SALT 0 NO_SOLVATE 0 312.4458CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@H]34)[C@@H]1CC[C@@]2(O)C#C NORGESTREL SJ000285678-2 SJ000285678 MICROSOURCE 1500460 NO_SALT 0 NO_SOLVATE 0 128.5563 Oc1ccc(Cl)cc1 PARACHLOROPHENOL SJ000285683-5 SJ000285683 SIGMA P 3510 CHLORIDE 1 NO_SOLVATE 0 374.885 COc1ccc(Cc2nccc3cc(OC)c(OC)cc23)cc1OC PAPAVERINE HYDROCHLORIDE SJ000285684-2 SJ000285684 MICROSOURCE 1500451 NO_SALT 0 NO_SOLVATE 0 228.2432 COc1ccc(C(=O)c2ccccc2)c(O)c1 OXYBENZONE SJ000285686-5 SJ000285686 SIGMA B 5399 NO_SALT 0 NO_SOLVATE 0 213.6607 NCC(CC(=O)O)c1ccc(Cl)cc1 BACLOFEN SJ000285687-2 SJ000285687 MICROSOURCE 1500146 CHLORIDE 1 NO_SOLVATE 0 196.7215 CC(C[N+](C)(C)C)OC(=O)N BETHANECHOL SJ000285688-2 SJ000285688 MICROSOURCE 1500137 CHLORIDE 1 NO_SOLVATE 0 292.7432 NC(CO)C(=O)NNCc1ccc(O)c(O)c1O BENSERAZIDE HYDROCHLORIDE SJ000285689-1 SJ000285689 MICROSOURCE 1500139 NO_SALT 0 NO_SOLVATE 0 165.1891 CCOC(=O)c1ccc(N)cc1 BENZOCAINE SJ000285692-2 SJ000285692 MICROSOURCE 1500144 NO_SALT 0 NO_SOLVATE 0C[C@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O 392.461 )C[C@]2(C)[C@@]1(O)C(=O)COBETAMETHASONE SJ000285695-1 SJ000285695 MICROSOURCE 1500158 CHLORIDE 1 NO_SOLVATE 0 182.6949 C[N+](C)(C)CCOC(=O)N CARBACHOL SJ000285696-1 SJ000285696 MICROSOURCE 1500159 NO_SALT 0 NO_SOLVATE 0 236.2685 NC(=O)N1c2ccccc2C=Cc3ccccc13 CARBAMAZEPINE SJ000285704-1 SJ000285704 MICROSOURCE 1500168 NO_SALT 0 NO_SOLVATE 0 349.4047 CC1=C(N2C(SC1)[C@H](NC(=O)[C@H](N)C3=CCC=CC3)C2=O)C(=O)O CEFRADINE SJ000285710-2 SJ000285710 MICROSOURCE 1500189 2-HYDROXYETHANAMINIUM 1 NO_SOLVATE 0 269.3688 CC1=CC(=O)N(O)C(=C1)C2CCCCC2 CICLOPIROX SJ000285712-2 SJ000285712 MICROSOURCE 1500196 CITRATE 1 NO_SOLVATE 0 595.0596 CCN(CC)CCOc1ccc(cc1)\C(=C(/Cl)\c2ccccc2)\c3ccccc3 CLOMIPHENE SJ000285713-5 SJ000285713 SIGMA C 6019 NO_SALT 0 NO_SOLVATE 0 344.8367 Clc1ccccc1C(c2ccccc2)(c3ccccc3)n4ccnc4 CLOTRIMAZOLE SJ000285715-2 SJ000285715 MICROSOURCE 1500202 NO_SALT 0 NO_SOLVATE 0 179.603 Oc1ccc(Cl)c2cccnc12 CLOXYQUIN SJ000285718-2 SJ000285718 MICROSOURCE 1500218 NO_SALT 0 NO_SOLVATE 0 182.1832 CN(C)N=Nc1[nH]cnc1C(=O)N DACARBAZINE SJ000285725-3 SJ000285725 PRESTWICK 725 METHANESULFONATE 1 NO_SOLVATE 0 655.784CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN DEFEROXAMINE SJ000285727-5 SJ000285727 SIGMA D 6140 CHLORIDE 1 NO_SOLVATE 0CN(C)[C@H]1[C@@H]2C[C@@H]3[C@H](O)c4c(Cl)ccc(O)c4C(=C3C(= 500.353 O)[C@]2(O)C(=C(C(=O)N)C1=O)O)ODEMECLOCYCLINE HYDROCHLORIDE SJ000285728-2 SJ000285728 MICROSOURCE 1500231 NO_SALT 0 NO_SOLVATE 0C[C@@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H]( 434.4977 O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)CDEXAMETHASONE ACETATE SJ000285729-2 SJ000285729 MICROSOURCE 1500232 SODIUM(I) 2 NO_SOLVATE 0 C[C@@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](518.4409 O)C[C@]2(C)[C@@]1(O)C(=O)COP(=O)(O)ODEXAMETHASONE Name of clinical anti-leukemic agent sample WT_EC 50 WT_EC 50 CI WT_curveScore WT_actclass T315I_EC 50 T315I_EC 50 CI T315I_curveScore T315I_actclass CYTARABINE SJ000285188-6 0.0639 0.0425 - 0.0961 A113 HIGH 0.0603 0.0355 - 0.1023 A113 HIGH MELPHALAN* SJ000285194-4 >5 NA C555 WEAK 3.9408 NA C555 WEAK MERCAPTOPURINE SJ000285195-2 0.0211 0.0013 - 0.3518 A111 HIGH 0.0444 0.0342 - 0.0575 B110 HIGH METHOTREXATE SJ000285196-2 0.0225 0.0014 - 0.3699 A111 HIGH 0.0438 0.0316 - 0.0606 A112 HIGH THIOGUANINE SJ000285208-3 0.0441 0.0248 - 0.0786 B110 HIGH 0.0202 0.0010 - 0.4084 B110 HIGH AMINOPTRINE SJ000285221-4 <0.1 NA B110 HIGH <0.1 NA B110 HIGH AZACITIDINE SJ000285227-1 1.2936 0.9338 - 1.7920 B311 WEAK 1.2871 0.8082 - 2.0498 B311 WEAK ETOPOSIDE SJ000285235-3 0.1369 0.1148 - 0.1632 A212 MED 0.1368 0.1164 - 0.1608 A212 MED MITOXANTRONE SJ000285321-4 0.0433 0.0348 - 0.0539 A112 HIGH 0.044 0.0361 - 0.0536 A112 HIGH HYDROCORTISONE SJ000285358-5 0.1905 0.1782 - 0.2036 A212 MED 0.19 0.1788 - 0.2020 A212 MED PREDNISOLONE SJ000285541-3 0.1573 0.1495 - 0.1654 A212 MED 0.1541 0.1406 - 0.1689 A212 MED DEXAMETHASONE SJ000285729-2 <0.1 0.0039 - 4.1318 B110 HIGH 0.0374 0.0102 - 0.1371 B110 HIGH AMSACRINE SJ000285974-2 0.0861 0.0767 - 0.0967 A112 HIGH 0.0747 0.0627 - 0.0889 A112 HIGH IDARUBICIN SJ000287925-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH VINCRISTINE SJ000288244-2 0.1045 0.0914 - 0.1194 A213 MED 0.1311 0.0021 - 8.2851 A214 MED

*often performs poorly in HTS sample WT_EC 50 WT_EC 50 CI WT_curveScore WT_actclass T315I_EC 50 T315I_EC 50 CI T315I_curveScore T315I_actclass comment SJ000000250-8 >5 NA B241 INACTIVE >5 NA D555 INACTIVE SJ000000854-6 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000113084-4 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000126662-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285182-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285183-2 0.2213 0.1535 - 0.3190 A211 MED 0.21 0.1479 - 0.2981 A212 MED SJ000285185-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285188-6 0.0639 0.0425 - 0.0961 A113 HIGH 0.0603 0.0355 - 0.1023 A113 HIGH SJ000285190-2 0.7932 0.7229 - 0.8703 A212 MED 0.7231 0.6469 - 0.8083 A212 MED SJ000285193-1 2.1027 2.0841 - 2.1214 B313 WEAK 2.285 2.2763 - 2.2937 B313 WEAK SJ000285194-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285194-4 >5 NA C555 WEAK 3.9408 NA C555 WEAK SJ000285195-2 0.0211 0.0013 - 0.3518 A111 HIGH 0.0444 0.0342 - 0.0575 B110 HIGH SJ000285196-2 0.0225 0.0014 - 0.3699 A111 HIGH 0.0438 0.0316 - 0.0606 A112 HIGH SJ000285197-1 0.1499 0.1248 - 0.1800 A212 MED 0.1542 0.1235 - 0.1926 A212 MED SJ000285200-6 1.2025 0.8162 - 1.7718 B311 WEAK 1.1389 0.8043 - 1.6128 B311 WEAK SJ000285202-2 1.8339 1.7982 - 1.8703 B313 WEAK 1.7597 1.6984 - 1.8232 A313 WEAK SJ000285203-5 <0.1 NA B110 HIGH 0.0824 0.0695 - 0.0978 A111 HIGH SJ000285206-2 >5 NA NC555 INACTIVE >5 NA C555 INACTIVE SJ000285207-1 0.4043 0.3822 - 0.4278 A213 MED 0.4118 0.3793 - 0.4471 A213 MED SJ000285208-3 0.0441 0.0248 - 0.0786 B110 HIGH 0.0202 0.0010 - 0.4084 B110 HIGH SJ000285210-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285212-1 1.6282 1.5516 - 1.7085 A313 WEAK 1.7678 1.7312 - 1.8052 B313 WEAK SJ000285215-1 1.0484 0.8816 - 1.2467 A313 WEAK 1.0426 0.8815 - 1.2333 A313 WEAK SJ000285215-6 0.0552 0.0513 - 0.0594 A113 HIGH 0.0527 0.0477 - 0.0583 A113 HIGH SJ000285218-5 >5 NA B332 INACTIVE >5 NA C555 INACTIVE SJ000285219-2 2.0837 2.0004 - 2.1703 B312 WEAK 1.7397 1.5755 - 1.9210 B312 WEAK SJ000285219-5 2.9391 2.8596 - 3.0208 B312 WEAK 2.8605 2.7902 - 2.9326 B312 WEAK SJ000285220-5 >5 NA C555 WEAK 2.8062 0.5197 - 15.1529 B314 WEAK SJ000285221-4 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285225-2 0.1607 0.1521 - 0.1698 A212 MED 0.1603 0.1544 - 0.1665 A213 MED SJ000285226-6 >5 NA B130 INACTIVE >5 NA A231 INACTIVE SJ000285227-1 1.2936 0.9338 - 1.7920 B311 WEAK 1.2871 0.8082 - 2.0498 B311 WEAK SJ000285228-4 0.3344 0.3149 - 0.3551 A211 MED 0.4033 0.3922 - 0.4148 A211 MED SJ000285229-2 1.9757 1.9316 - 2.0207 B322 WEAK 1.9622 1.8651 - 2.0644 B322 WEAK SJ000285231-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285232-1 0.117 0.1002 - 0.1366 A213 MED 0.1133 0.0999 - 0.1285 A213 MED SJ000285232-8 0.0619 0.0351 - 0.1092 A114 HIGH 0.0566 0.0444 - 0.0721 A114 HIGH SJ000285234-2 0.3225 0.2286 - 0.4550 A211 MED 0.3737 0.3442 - 0.4058 A211 MED SJ000285235-3 0.1369 0.1148 - 0.1632 A212 MED 0.1368 0.1164 - 0.1608 A212 MED SJ000285238-3 0.1022 0.0880 - 0.1188 A213 MED 0.1214 0.0955 - 0.1542 A214 MED SJ000285241-3 0.1569 0.1188 - 0.2071 B110 MED 0.1024 0.0737 - 0.1421 A211 MED SJ000285242-3 4.4693 NA C555 WEAK >5 NA C555 INACTIVE Differential activity within experimental error SJ000285243-2 0.48 0.4327 - 0.5325 A213 MED 0.4074 0.3682 - 0.4508 A213 MED SJ000285244-3 1.5123 1.4902 - 1.5347 A313 WEAK 1.7214 1.6838 - 1.7597 A313 WEAK SJ000285246-2 0.8225 0.6899 - 0.9806 A212 MED 0.9896 0.8088 - 1.2108 A212 MED SJ000285249-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285256-3 0.3341 0.2737 - 0.4077 A212 MED 0.3286 0.2649 - 0.4076 A212 MED SJ000285261-3 0.2342 0.1932 - 0.2840 A213 MED 0.2457 0.1708 - 0.3535 A214 MED SJ000285262-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000285263-2 >5 NA D555 INACTIVE >5 NA A241 INACTIVE SJ000285267-3 0.0853 0.0560 - 0.1301 A112 HIGH 0.1561 0.1245 - 0.1956 A212 MED Differential activity within experimental error SJ000285270-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285272-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285273-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285276-2 4.0523 NA C555 WEAK 3.1302 2.9524 - 3.3187 B312 WEAK SJ000285278-1 <1.0 NA C555 MED <1.0 NA C555 MED SJ000285279-2 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000285285-3 >5 NA B141 INACTIVE >5 NA B241 INACTIVE SJ000285292-10 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000285294-1 0.074 0.0659 - 0.0830 A113 HIGH 0.0742 0.0666 - 0.0828 A113 HIGH SJ000285299-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285307-3 >5 NA B344 INACTIVE >5 NA B334 INACTIVE SJ000285308-1 0.5458 0.5060 - 0.5886 A213 MED 0.5062 0.4281 - 0.5985 A213 MED SJ000285313-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285315-2 1.0561 1.0324 - 1.0803 B312 WEAK 0.7384 0.6862 - 0.7946 A212 MED Differential activity within experimental error SJ000285316-4 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285317-2 >5 NA NC555 INACTIVE 3.8254 NA C555 WEAK Differential activity within experimental error SJ000285318-7 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285319-1 1.7406 1.6595 - 1.8256 A314 WEAK 2.0096 1.9300 - 2.0925 B314 WEAK SJ000285321-4 0.0433 0.0348 - 0.0539 A112 HIGH 0.044 0.0361 - 0.0536 A112 HIGH SJ000285323-3 >5 NA B332 INACTIVE >5 NA B321 INACTIVE SJ000285327-1 1.6528 1.6211 - 1.6851 A313 WEAK 1.8204 1.7962 - 1.8449 B313 WEAK SJ000285332-1 0.1515 0.1256 - 0.1826 A212 MED 0.2075 0.1841 - 0.2338 A212 MED SJ000285334-4 >5 NA C555 INACTIVE 0 NA C555 INACTIVE SJ000285335-1 0.0666 0.0196 - 0.2261 A114 HIGH 0.0687 0.0028 - 1.6949 A114 HIGH SJ000285335-4 0.1386 0.0008 - 22.9222 A214 MED 0.1244 0.0676 - 0.2290 A214 MED SJ000285337-5 >5 NA B342 INACTIVE >5 NA D555 INACTIVE SJ000285337-8 >5 NA B140 INACTIVE >5 NA A241 INACTIVE SJ000285338-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285343-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285358-5 0.1905 0.1782 - 0.2036 A212 MED 0.19 0.1788 - 0.2020 A212 MED SJ000285363-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285364-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285365-1 2.2925 1.1080 - 4.7433 B321 WEAK >5 NA B334 INACTIVE SJ000285368-3 >5 NA C555 WEAK >5 NA C555 WEAK SJ000285369-1 >5 NA C555 WEAK 3.9664 NA B313 WEAK SJ000285373-9 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285375-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285382-3 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000285383-1 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000285387-8 >5 NA NC555 INACTIVE >5 NA C555 INACTIVE SJ000285396-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285400-2 >5 NA B342 INACTIVE >5 NA B344 INACTIVE SJ000285410-5 0.0303 0.0268 - 0.0342 A113 HIGH 0.0276 0.0238 - 0.0319 B110 HIGH SJ000285413-1 0.9636 0.8101 - 1.1461 A214 MED 2.5855 NA C555 WEAK Differential activity within experimental error SJ000285423-2 0.9398 0.8608 - 1.0260 A212 MED 0.9064 0.7444 - 1.1035 A212 MED SJ000285426-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285431-2 >5 NA D555 INACTIVE >5 NA NB142 INACTIVE SJ000285433-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285436-3 1.1776 1.1246-1.2303 A322 WEAK 1.183 1.1246-1.2445 A322 WEAK ARTEMISININ SJ000285439-2 >5 NA C555 INACTIVE >5 NA B313 INACTIVE SJ000285440-2 2.6129 2.3056 - 2.9611 B312 WEAK 1.7108 1.0736 - 2.7263 B311 WEAK SJ000285442-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285443-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285445-2 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000285450-2 >5 NA C555 WEAK >5 NA C555 WEAK Differential activity within experimental error SJ000285451-3 1.5777 1.1606 - 2.1448 B321 WEAK 4.852 NA C555 WEAK SJ000285452-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285452-5 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285453-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285454-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285460-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285461-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285462-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285465-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285466-4 0.1742 0.1186 - 0.2559 A211 MED 0.1286 0.0965 - 0.1716 B110 MED SJ000285484-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285487-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285490-1 1.5512 1.5019 - 1.6022 A313 WEAK >5 NA B333 INACTIVE Significant shift in efficacy, not potency SJ000285502-5 >5 NA B342 INACTIVE >5 NA C555 INACTIVE SJ000285504-2 >5 NA C555 INACTIVE >5 NA A241 INACTIVE SJ000285506-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285508-1 0.2163 0.1969 - 0.2377 A213 MED 0.2332 0.2081 - 0.2613 A213 MED SJ000285512-1 3.5581 3.5015 - 3.6156 B313 WEAK 4.287 NA C555 WEAK SJ000285522-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285526-3 >5 NA A241 INACTIVE >5 NA B241 INACTIVE SJ000285536-1 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000285540-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285541-3 0.1573 0.1495 - 0.1654 A212 MED 0.1541 0.1406 - 0.1689 A212 MED SJ000285542-2 0.1346 0.1233 - 0.1468 A212 MED 0.1274 0.1191 - 0.1363 A212 MED SJ000285543-1 >5 NA A242 INACTIVE >5 NA B331 INACTIVE SJ000285544-3 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000285547-5 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000285549-5 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000285551-2 >5 NA C555 INACTIVE >5 NA A242 INACTIVE SJ000285554-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285564-2 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000285569-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285572-3 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000285572-4 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285574-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285577-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285584-1 >5 NA C555 INACTIVE >5 NA B141 INACTIVE SJ000285586-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285587-1 0.2018 0.0239 - 1.7053 A211 MED 0.2793 0.0259 - 3.0073 A211 MED SJ000285588-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000285591-1 >5 NA C555 WEAK 3.2243 2.9841 - 3.4838 B312 WEAK SJ000285592-5 >5 NA C555 INACTIVE >5 NA B344 INACTIVE SJ000285606-5 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285608-2 >5 NA A241 INACTIVE >5 NA B341 INACTIVE SJ000285608-4 >5 NA C555 INACTIVE >5 NA B341 INACTIVE SJ000285610-5 >5 NA C555 INACTIVE >5 NA B344 INACTIVE SJ000285614-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285618-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285619-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285625-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285630-6 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285635-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285638-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285643-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285646-1 0.2119 0.1898 - 0.2367 A212 MED 0.1965 0.1746 - 0.2213 A212 MED SJ000285651-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285652-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285655-1 >5 NA B243 INACTIVE >5 NA B241 INACTIVE SJ000285657-1 0.1253 0.1140 - 0.1376 A212 MED 0.125 0.1179 - 0.1324 A212 MED SJ000285659-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285664-3 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285666-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285667-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285668-3 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285671-2 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000285674-3 >5 NA A241 INACTIVE >5 NA B241 INACTIVE SJ000285678-2 >5 NA B141 INACTIVE >5 NA C555 INACTIVE SJ000285683-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285684-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285686-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285687-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285688-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285689-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285692-2 0.0399 0.0322 - 0.0495 A112 HIGH 0.0358 0.0302 - 0.0424 A113 HIGH SJ000285695-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285696-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285704-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285710-2 1.4543 1.3330 - 1.5866 A312 WEAK 1.2069 1.1588 - 1.2569 A313 WEAK SJ000285712-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285713-5 >5 NA C555 INACTIVE >5 NA B314 INACTIVE SJ000285715-2 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000285718-2 2.9705 2.5382 - 3.4763 B322 WEAK >5 NA B322 INACTIVE Differential activity within experimental error SJ000285725-3 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000285727-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285728-2 0.0349 0.0313 - 0.0390 B110 HIGH 0.0363 0.0314 - 0.0420 A112 HIGH SJ000285729-2 <0.1 0.0039 - 4.1318 B110 HIGH 0.0374 0.0102 - 0.1371 B110 HIGH SJ000285740-1 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000285742-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285745-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285747-3 0.1383 0.1316 - 0.1452 A213 MED 0.1465 0.1407 - 0.1526 A213 MED SJ000285748-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285750-1 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000285752-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285761-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285764-3 4.1895 NA C555 WEAK >5 NA C555 WEAK SJ000285766-1 0.0442 0.0401 - 0.0487 B110 HIGH 0.046 0.0427 - 0.0495 A113 HIGH SJ000285767-2 0.0214 0.0184 - 0.0249 B110 HIGH 0.0255 0.0228 - 0.0285 A113 HIGH SJ000285768-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285769-1 0.0406 0.0358 - 0.0459 A112 HIGH 0.0434 0.0403 - 0.0468 A113 HIGH SJ000285770-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285778-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285781-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285783-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285786-2 0.1307 0.0938 - 0.1821 A212 MED 0.1136 0.0838 - 0.1538 A213 MED SJ000285787-2 0.8184 0.7921 - 0.8455 A213 MED 0.8671 0.8509 - 0.8837 A213 MED SJ000285787-4 0.5572 0.5418 - 0.5729 A213 MED 0.5282 0.5051 - 0.5523 A213 MED SJ000285790-1 2.5093 2.4752 - 2.5439 B313 WEAK 2.9331 2.8664 - 3.0014 B313 WEAK SJ000285797-2 >5 NA A243 INACTIVE >5 NA C555 INACTIVE SJ000285801-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285812-1 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000285814-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285814-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285818-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285820-1 0.0416 0.0213 - 0.0814 A111 HIGH 0.0512 0.0395 - 0.0664 A112 HIGH SJ000285827-2 1.5678 1.1031 - 2.2285 B311 WEAK >5 NA C555 WEAK SJ000285831-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285834-1 >5 NA B341 INACTIVE >5 NA D555 INACTIVE SJ000285835-2 >5 NA C555 INACTIVE >5 NA B244 INACTIVE SJ000285836-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285837-1 >5 NA B313 INACTIVE >5 NA C555 INACTIVE SJ000285838-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285840-2 0.9191 0.8184 - 1.0322 A214 MED 0.8819 0.8216 - 0.9466 A214 MED SJ000285842-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285845-5 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000285849-3 0.4435 0.3978 - 0.4944 A212 MED 0.4338 0.3884 - 0.4846 A212 MED SJ000285858-5 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000285860-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285864-3 1.2127 1.1502 - 1.2785 A313 WEAK 1.3427 1.2789 - 1.4096 A313 WEAK SJ000285866-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285878-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285879-3 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285880-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285881-1 3.1053 2.9783 - 3.2377 B312 WEAK 2.3759 2.3476 - 2.4045 B313 WEAK SJ000285882-2 >5 NA A242 INACTIVE >5 NA C555 INACTIVE SJ000285885-5 >5 NA NA241 INACTIVE >5 NA D555 INACTIVE SJ000285887-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285888-1 >5 NA C555 WEAK >5 NA B313 WEAK SJ000285890-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285892-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285903-2 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000285909-2 >5 NA A242 INACTIVE >5 NA D555 INACTIVE SJ000285920-5 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000285922-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285925-2 >5 NA B241 INACTIVE >5 NA D555 INACTIVE SJ000285935-1 >5 NA C555 INACTIVE >5 NA B344 INACTIVE SJ000285936-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285940-2 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000285949-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285950-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285951-3 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000285958-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000285959-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000285960-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000285965-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285966-2 1.2967 0.7065 - 2.3798 A314 WEAK 2.0144 1.9973 - 2.0317 B312 WEAK SJ000285967-1 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000285971-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000285972-1 4.2077 NA C555 WEAK 2.4586 2.4189 - 2.4989 B312 WEAK SJ000285973-2 0.1698 0.1572 - 0.1833 A212 MED 0.1623 0.1542 - 0.1709 A212 MED SJ000285974-2 0.0861 0.0767 - 0.0967 A112 HIGH 0.0747 0.0627 - 0.0889 A112 HIGH SJ000285978-2 0.2212 0.1336 - 0.3662 A211 MED 0.1961 0.1048 - 0.3669 A211 MED SJ000285980-3 4.2933 NA C555 WEAK 3.3236 3.1759 - 3.4782 B312 WEAK SJ000285983-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285987-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285991-2 1.1053 0.7753 - 1.5756 B311 WEAK 0.7808 0.7463 - 0.8169 A212 MED Differential activity within experimental error SJ000285996-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000285998-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000285999-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286003-2 0.7272 0.2263 - 2.3376 A211 MED 0.3626 0.3272 - 0.4017 A211 MED SJ000286004-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286006-3 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286007-1 1.0062 0.8964 - 1.1294 A313 WEAK 0.9628 0.8199 - 1.1308 A212 MED Differential activity within experimental error SJ000286008-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286018-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286024-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286025-1 >5 NA C555 INACTIVE >5 NA B332 INACTIVE SJ000286030-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286034-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286035-1 >5 NA D555 INACTIVE >5 NA B341 INACTIVE SJ000286036-1 >5 NA B143 INACTIVE >5 NA C555 INACTIVE SJ000286037-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286038-1 0.0931 0.0858 - 0.1010 A113 HIGH 0.0782 0.0723 - 0.0846 A113 HIGH SJ000286038-4 0.0508 0.0445 - 0.0581 A113 HIGH 0.0578 0.0515 - 0.0649 A113 HIGH SJ000286039-3 0.0238 0.0179 - 0.0317 B110 HIGH 0.021 0.0145 - 0.0303 B110 HIGH SJ000286041-1 >5 NA B141 INACTIVE >5 NA B341 INACTIVE SJ000286044-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286046-7 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286046-9 >5 NA C555 INACTIVE >5 NA A241 INACTIVE SJ000286052-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286053-3 >5 NA B332 INACTIVE >5 NA B321 INACTIVE SJ000286056-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286057-2 >5 NA C555 WEAK 2.4313 2.4033 - 2.4597 B312 WEAK SJ000286063-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000286065-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286075-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286086-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286093-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286097-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286098-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286101-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286109-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286112-2 >5 NA C555 WEAK >5 NA C555 WEAK SJ000286113-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286118-3 >5 NA D555 INACTIVE >5 NA A344 INACTIVE SJ000286121-3 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286124-1 >5 NA C555 INACTIVE >5 NA B341 INACTIVE SJ000286127-5 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286128-2 0.4695 0.3938 - 0.5597 A213 MED 0.4789 0.3911 - 0.5864 A213 MED SJ000286133-5 >5 NA C555 INACTIVE >5 NA B343 INACTIVE SJ000286134-5 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286142-2 0.4718 0.4465 - 0.4984 A213 MED 0.4944 0.4672 - 0.5231 A212 MED SJ000286143-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286144-3 1.2315 1.1244 - 1.3489 B312 WEAK 1.1138 0.9772 - 1.2695 B312 WEAK SJ000286146-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286151-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286152-2 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000286154-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286155-5 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000286156-2 1.0381 0.8985 - 1.1994 A313 WEAK 1.0097 0.8164 - 1.2487 A313 WEAK SJ000286159-2 0.2887 0.2448 - 0.3404 A212 MED 0.3018 0.2554 - 0.3567 A212 MED SJ000286160-1 0.4594 0.3777 - 0.5586 A211 MED 0.3036 0.2841 - 0.3245 A213 MED SJ000286162-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286166-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286172-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286174-2 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000286175-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286178-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286181-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286185-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286186-3 2.4152 2.3733 - 2.4579 B313 WEAK 2.4276 1.7583 - 3.3517 B314 WEAK SJ000286187-2 0.9432 0.8364 - 1.0635 A213 MED 0.9116 0.8686 - 0.9568 A213 MED SJ000286188-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286191-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286195-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286199-2 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000286204-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286205-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286213-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286217-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286225-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286229-4 >5 NA A242 INACTIVE >5 NA A241 INACTIVE SJ000286231-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286236-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286243-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286248-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286251-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286267-1 >5 NA C555 WEAK 4.6918 NA C555 WEAK SJ000286300-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000286312-1 >5 NA C555 INACTIVE >5 NA B344 INACTIVE SJ000286359-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286366-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286380-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286381-1 0.1792 0.1603 - 0.2003 A222 MED 0.329 0.0988 - 1.0953 A234 MED SJ000286382-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286387-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286389-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286393-1 4.6178 NA C555 WEAK >5 NA C555 INACTIVE Differential activity within experimental error SJ000286395-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286396-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286398-1 2.0556 1.9918 - 2.1214 B313 WEAK 2.928 2.8242 - 3.0356 B312 WEAK SJ000286406-1 0.9532 0.9390 - 0.9676 A213 MED 1.0358 0.9951 - 1.0783 A312 MED SJ000286408-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286413-1 >5 NA C555 WEAK 3.4496 3.4248 - 3.4745 B313 WEAK SJ000286415-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286419-1 >5 NA B241 INACTIVE >5 NA D555 INACTIVE SJ000286421-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286423-1 2.0321 1.9745 - 2.0914 B314 WEAK 2.0036 1.9296 - 2.0805 B314 WEAK SJ000286424-1 0.314 0.1913 - 0.5154 A221 MED 0.7253 0.6854 - 0.7675 A212 MED SJ000286430-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000286434-1 1.6319 1.6097 - 1.6545 B313 WEAK 1.4706 1.3664 - 1.5827 B312 WEAK SJ000286436-1 <0.1 NA B110 HIGH 0.1213 0.1021 - 0.1440 B110 MED Differential activity within experimental error SJ000286438-1 >5 NA B321 INACTIVE >5 NA C555 INACTIVE SJ000286446-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286448-1 0.1447 0.1099 - 0.1906 A212 MED 0.1909 0.1448 - 0.2516 A212 MED SJ000286450-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286451-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286453-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286455-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286458-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286481-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286496-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286501-2 >5 NA B314 INACTIVE >5 NA C555 INACTIVE SJ000286511-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286515-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286515-2 0.0648 0.0536 - 0.0783 A113 HIGH 0.0651 0.0561 - 0.0754 A113 HIGH SJ000286516-4 >5 NA C555 INACTIVE >5 NA B313 INACTIVE SJ000286520-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286522-1 4.0011 NA C555 WEAK 2.834 2.6811 - 2.9956 B312 WEAK SJ000286525-1 >5 NA B141 INACTIVE >5 NA C555 INACTIVE SJ000286530-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286533-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286536-1 0.7071 0.6825 - 0.7325 A212 MED 0.6411 0.6184 - 0.6645 A212 MED SJ000286537-1 0.3082 0.2752 - 0.3452 A221 MED 0.9009 0.7435 - 1.0917 A222 MED SJ000286548-2 2.0459 1.9915 - 2.1018 B322 WEAK 2.2948 2.2635 - 2.3267 B312 WEAK SJ000286550-2 >5 NA NB241 INACTIVE >5 NA D555 INACTIVE SJ000286552-1 0.0503 0.0427 - 0.0592 B110 HIGH 0.042 0.0353 - 0.0499 B110 HIGH SJ000286565-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286572-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286576-1 0.8303 0.7823 - 0.8814 A212 MED 0.7585 0.7253 - 0.7932 A212 MED SJ000286594-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286616-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286619-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286644-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286645-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286646-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286648-1 >5 NA B141 INACTIVE >5 NA C555 INACTIVE SJ000286657-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286658-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286694-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286708-1 3.054 2.3308 - 4.0015 B313 WEAK 2.6085 2.1808 - 3.1201 B314 WEAK SJ000286710-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286711-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286715-2 1.9516 1.8621 - 2.0453 B312 WEAK 2.4069 2.3605 - 2.4543 B312 WEAK SJ000286728-1 0.2169 0.1313 - 0.3584 A211 MED 0.3591 0.3283 - 0.3927 A212 MED SJ000286729-1 >5 NA D555 INACTIVE >5 NA B141 INACTIVE SJ000286749-1 3.0281 2.9392 - 3.1196 B312 WEAK 2.4661 2.4380 - 2.4945 B312 WEAK SJ000286751-1 0.2951 0.1510 - 0.5765 A212 MED 0.2616 0.1867 - 0.3665 A212 MED SJ000286753-1 0.721 0.6923 - 0.7509 A213 MED 0.808 0.7737 - 0.8438 A213 MED SJ000286767-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286769-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286772-1 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000286775-1 >5 NA B314 INACTIVE >5 NA C555 INACTIVE SJ000286776-1 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000286780-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286781-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286782-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286783-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286797-1 >5 NA C555 INACTIVE >5 NA B314 INACTIVE SJ000286800-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286801-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286802-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286804-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286809-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286813-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286816-1 1.1816 0.5135 - 2.7190 B311 WEAK 2.1215 1.3636 - 3.3006 B311 WEAK SJ000286821-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286829-2 >5 NA B241 INACTIVE >5 NA A241 INACTIVE SJ000286830-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286847-1 0.3333 0.3014 - 0.3686 A232 WEAK 0.6878 0.5576 - 0.8483 A233 WEAK SJ000286853-1 >5 NA B241 INACTIVE >5 NA A242 INACTIVE SJ000286865-1 >5 NA D555 INACTIVE >5 NA NA141 INACTIVE SJ000286868-1 >5 NA A241 INACTIVE >5 NA D555 INACTIVE SJ000286877-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286884-1 >5 NA B141 INACTIVE >5 NA D555 INACTIVE SJ000286890-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000286899-6 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286902-2 0.1882 0.1689 - 0.2098 A212 MED 0.1934 0.1731 - 0.2160 A212 MED SJ000286904-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000286906-1 >5 NA A242 INACTIVE >5 NA D555 INACTIVE SJ000286948-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000286950-4 2.7871 2.6267 - 2.9574 B312 WEAK >5 NA C555 INACTIVE SJ000286959-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000286960-1 2.0573 2.0333 - 2.0817 B313 WEAK 1.9578 1.9446 - 1.9711 B313 WEAK SJ000286962-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000286963-1 >5 NA C555 INACTIVE >5 NA B334 INACTIVE SJ000286965-1 <0.1 NA C555 HIGH <0.1 NA C555 HIGH SJ000286983-2 0.0323 0.0238 - 0.0438 B110 HIGH 0.0213 0.0159 - 0.0287 B110 HIGH SJ000286986-1 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000286993-1 1.03 0.8297 - 1.2786 A312 WEAK 1.3651 1.1879 - 1.5686 B312 WEAK SJ000287007-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287016-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287020-1 >5 NA D555 INACTIVE >5 NA NB141 INACTIVE SJ000287054-1 >5 NA A241 INACTIVE >5 NA D555 INACTIVE SJ000287055-3 1.4999 1.3631 - 1.6505 B312 WEAK 1.291 0.7246 - 2.3002 A324 WEAK SJ000287058-1 >5 NA B141 INACTIVE >5 NA A241 INACTIVE SJ000287059-1 0.3416 0.3018 - 0.3866 A221 MED 2.4681 1.2594 - 4.8369 B311 WEAK Differential activity within experimental error SJ000287062-1 >5 NA C555 WEAK 2.3374 2.3101 - 2.3651 B313 WEAK SJ000287073-2 >5 NA A241 INACTIVE >5 NA B244 INACTIVE SJ000287074-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287076-4 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287077-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287078-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287087-1 1.9311 1.8976 - 1.9652 B313 WEAK 1.9031 1.8028 - 2.0090 B313 WEAK SJ000287088-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287090-1 >5 NA A233 INACTIVE 1.2339 0.8712 - 1.7477 A324 WEAK Differential activity within experimental error SJ000287092-1 0.1214 0.0807 - 0.1827 A213 MED 0.1039 0.0705 - 0.1531 A212 MED SJ000287098-4 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000287101-1 >5 NA B341 INACTIVE >5 NA C555 INACTIVE SJ000287102-1 0.0362 0.0314 - 0.0418 B110 HIGH 0.0365 0.0165 - 0.0806 B110 HIGH SJ000287131-1 >5 NA NB144 INACTIVE >5 NA C555 INACTIVE SJ000287132-2 >5 NA A141 INACTIVE >5 NA A241 INACTIVE SJ000287133-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287134-1 1.4028 1.1796 - 1.6684 B312 WEAK 1.2957 1.1132 - 1.5081 B312 WEAK SJ000287136-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287138-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287139-1 >5 NA C555 WEAK >5 NA C555 WEAK SJ000287147-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287149-1 <1.0 NA C555 MED <1.0 NA C555 MED SJ000287150-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287152-1 0.3768 0.3328 - 0.4266 A212 MED 0.3899 0.3213 - 0.4731 A212 MED SJ000287155-1 0.078 0.0708 - 0.0858 A112 HIGH 0.0669 0.0607 - 0.0738 A113 HIGH SJ000287160-1 1.8786 1.8381 - 1.9199 B312 WEAK 2.2265 2.1794 - 2.2747 B312 WEAK SJ000287177-1 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000287181-1 >5 NA C555 INACTIVE >5 NA A241 INACTIVE SJ000287182-5 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000287193-3 >5 NA B314 INACTIVE >5 NA D555 INACTIVE SJ000287195-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287203-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287206-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287209-1 1.754 1.6223 - 1.8964 B312 WEAK 2.295 2.1725 - 2.4243 B312 WEAK SJ000287215-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287222-1 0.0618 0.0510 - 0.0749 A112 HIGH 0.0575 0.0479 - 0.0689 A112 HIGH SJ000287228-1 2.055 2.0312 - 2.0791 B312 WEAK >1.0 0.0010 - 699.2647 A214 WEAK SJ000287229-1 >5 NA B241 INACTIVE >5 NA D555 INACTIVE SJ000287231-1 0.0909 0.0792 - 0.1044 A112 HIGH 0.0837 0.0727 - 0.0963 A112 HIGH SJ000287238-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287239-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287245-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287247-1 0.0671 0.0513 - 0.0878 B110 HIGH 0.0582 0.0412 - 0.0823 B110 HIGH SJ000287256-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287261-1 0.1832 0.1553 - 0.2162 A212 MED 0.1749 0.1482 - 0.2063 A212 MED SJ000287270-1 0.4073 0.3609 - 0.4595 A212 MED 0.3365 0.2582 - 0.4385 A212 MED SJ000287281-1 >5 NA B343 INACTIVE >5 NA C555 INACTIVE SJ000287282-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287283-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287295-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287300-3 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000287313-1 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000287314-3 1.0237 NA C555 WEAK >5 NA D555 INACTIVE Differential activity within experimental error SJ000287317-4 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287320-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287329-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287330-1 2.8722 2.6847 - 3.0727 B312 WEAK 2.0003 1.9539 - 2.0478 B312 WEAK SJ000287331-1 0.2183 0.1905 - 0.2501 A212 MED 0.1906 0.1602 - 0.2267 A213 MED SJ000287333-1 0.0532 0.0458 - 0.0619 A113 HIGH 0.0577 0.0502 - 0.0663 A112 HIGH SJ000287335-1 >5 NA A241 INACTIVE >5 NA B241 INACTIVE SJ000287348-1 0.0807 0.0681 - 0.0956 A112 HIGH 0.0847 0.0705 - 0.1018 A112 HIGH SJ000287350-1 >5 NA B342 INACTIVE >5 NA C555 INACTIVE SJ000287365-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287368-1 1.0958 0.8387 - 1.4317 B311 WEAK 0.5999 0.5365 - 0.6708 A211 MED Differential activity within experimental error SJ000287384-1 1.0372 0.9357 - 1.1498 A322 WEAK 1.4013 1.3316 - 1.4747 B312 WEAK SJ000287393-1 0.0457 0.0382 - 0.0547 B110 HIGH 0.0452 0.0368 - 0.0554 B110 HIGH SJ000287394-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287395-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287397-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287398-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287400-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287409-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287413-2 >5 NA B343 INACTIVE >5 NA C555 INACTIVE SJ000287428-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287441-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287448-1 4.723 NA C555 WEAK >5 NA C555 INACTIVE Differential activity within experimental error SJ000287450-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287457-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287461-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287462-1 >5 NA B331 INACTIVE >5 NA B331 INACTIVE SJ000287467-3 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287484-1 >5 NA B241 INACTIVE >5 NA C555 INACTIVE SJ000287488-1 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287490-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287493-3 >5 NA C555 INACTIVE >5 NA B343 INACTIVE SJ000287506-1 >5 NA B130 INACTIVE >5 NA B130 INACTIVE SJ000287508-1 0.0223 0.0176 - 0.0283 B110 HIGH 0.0249 0.0201 - 0.0308 B110 HIGH SJ000287523-1 0.088 0.0770 - 0.1006 B110 HIGH 0.0797 0.0702 - 0.0905 A112 HIGH SJ000287543-1 >5 NA NA141 INACTIVE >5 NA D555 INACTIVE SJ000287544-1 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000287545-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287547-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287561-1 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000287562-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287563-1 0.1431 0.1270 - 0.1612 A213 MED 0.1397 0.1150 - 0.1698 A213 MED SJ000287568-1 0.0102 0.0086 - 0.0121 B110 HIGH 0.0069 0.0018 - 0.0267 B110 HIGH SJ000287585-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287590-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287618-2 >5 NA D555 INACTIVE >5 NA B341 INACTIVE SJ000287619-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287632-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287647-2 >5 NA B334 INACTIVE >5 NA C555 INACTIVE SJ000287648-2 >5 NA A241 INACTIVE >5 NA D555 INACTIVE SJ000287657-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287660-2 0.0659 0.0514 - 0.0847 A112 HIGH 0.0578 0.0446 - 0.0751 A112 HIGH SJ000287663-2 2.6629 1.6576 - 4.2777 B314 WEAK 2.5982 2.5103 - 2.6892 B314 WEAK SJ000287667-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287668-2 >5 NA C555 INACTIVE >5 NA A241 INACTIVE SJ000287676-2 1.7578 1.6958 - 1.8221 B313 WEAK 1.7042 1.6139 - 1.7996 B322 WEAK SJ000287677-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287680-3 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287682-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287686-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287690-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287692-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287693-2 >5 NA A344 INACTIVE >5 NA B342 INACTIVE SJ000287697-2 >5 NA B130 INACTIVE >5 NA C555 INACTIVE SJ000287703-2 >5 NA B343 INACTIVE >5 NA B343 INACTIVE SJ000287705-2 >5 NA C555 INACTIVE >5 NA B333 INACTIVE SJ000287706-2 >5 NA B334 INACTIVE >5 NA C555 INACTIVE SJ000287714-2 1.0777 0.3018 - 3.8488 A314 WEAK 1.692 1.0254 - 2.7920 B311 WEAK SJ000287728-2 1.6312 1.5355 - 1.7329 B312 WEAK 1.6193 1.4530 - 1.8047 B312 WEAK SJ000287730-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287734-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287737-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287741-2 0.4672 0.3855 - 0.5661 A213 MED 0.4667 0.3819 - 0.5704 A213 MED SJ000287744-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287749-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000287750-2 >5 NA B344 INACTIVE >5 NA C555 INACTIVE SJ000287752-2 >5 NA B342 INACTIVE >5 NA B341 INACTIVE SJ000287758-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287762-2 >5 NA B141 INACTIVE >5 NA B244 INACTIVE SJ000287767-2 >5 NA D555 INACTIVE >5 NA B341 INACTIVE SJ000287768-2 0.4478 0.4035 - 0.4969 A214 MED 0.4379 0.3997 - 0.4798 A213 MED SJ000287769-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287778-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287799-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287810-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287813-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287814-2 >5 NA B314 INACTIVE >5 NA C555 INACTIVE SJ000287821-2 >5 NA C555 INACTIVE >5 NA B313 INACTIVE SJ000287827-2 0.0471 0.0338 - 0.0657 B110 HIGH 0.0435 0.0345 - 0.0548 A112 HIGH SJ000287837-2 >5 NA B341 INACTIVE >5 NA C555 INACTIVE SJ000287841-2 >5 NA B342 INACTIVE >5 NA C555 INACTIVE SJ000287864-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287868-2 >5 NA B332 INACTIVE 2.2448 2.1303 - 2.3655 B314 WEAK Significant shift in efficacy, not potency SJ000287873-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287875-2 >5 NA NC555 INACTIVE >5 NA C555 INACTIVE SJ000287882-2 >5 NA D555 INACTIVE >5 NA NC555 INACTIVE SJ000287889-2 >5 NA B334 INACTIVE >5 NA C555 INACTIVE SJ000287891-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287899-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287901-2 >5 NA B342 INACTIVE >5 NA B332 INACTIVE SJ000287902-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287925-2 <0.1 NA B110 HIGH <0.1 NA B110 HIGH SJ000287942-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000287955-2 >5 NA B244 INACTIVE >5 NA A241 INACTIVE SJ000287956-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287970-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287972-2 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000287975-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000287985-2 >5 NA C555 INACTIVE >5 NA B344 INACTIVE SJ000287990-2 2.2004 2.1724 - 2.2288 B313 WEAK 2.2877 2.2204 - 2.3570 B313 WEAK SJ000287995-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288002-2 2.0053 1.9724 - 2.0387 B313 WEAK 2.0943 2.0403 - 2.1498 B314 WEAK SJ000288007-2 >5 NA C555 INACTIVE >5 NA B241 INACTIVE SJ000288017-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288020-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288025-2 >5 NA B342 INACTIVE >5 NA C555 INACTIVE SJ000288026-2 >5 NA NB241 INACTIVE >5 NA D555 INACTIVE SJ000288030-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000288031-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288034-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288037-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288041-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288052-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288058-2 >5 NA NA141 INACTIVE >5 NA D555 INACTIVE SJ000288059-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288063-2 1.202 1.0820 - 1.3352 B322 WEAK >5 NA A342 INACTIVE Significant shift in efficacy, not potency SJ000288073-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000288074-2 >5 NA A241 INACTIVE >5 NA C555 INACTIVE SJ000288081-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288084-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288092-2 >5 NA NB144 INACTIVE >5 NA D555 INACTIVE SJ000288093-2 >5 NA NB242 INACTIVE >5 NA D555 INACTIVE SJ000288098-2 >5 NA C555 INACTIVE >5 NA B342 INACTIVE SJ000288099-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288114-2 >5 NA D555 INACTIVE >5 NA B241 INACTIVE SJ000288126-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288139-2 >5 NA C555 WEAK 2.2411 2.2103 - 2.2723 B313 WEAK SJ000288140-2 >5 NA C555 INACTIVE >5 NA B314 INACTIVE SJ000288147-2 1.0095 0.6912 - 1.4743 A314 WEAK 0.9875 0.7673 - 1.2708 A214 MED Differential activity within experimental error SJ000288150-2 >5 NA B331 INACTIVE >5 NA B331 INACTIVE SJ000288156-2 >5 NA C555 INACTIVE >5 NA B323 INACTIVE SJ000288159-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288163-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288173-2 >5 NA C555 WEAK 1.4271 1.2596 - 1.6168 B311 WEAK SJ000288175-2 >5 NA NC555 INACTIVE >5 NA D555 INACTIVE SJ000288176-2 >5 NA C555 INACTIVE >5 NA B333 INACTIVE SJ000288181-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288182-2 >5 NA B241 INACTIVE >5 NA A241 INACTIVE SJ000288186-2 >5 NA A141 INACTIVE >5 NA C555 INACTIVE SJ000288194-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288209-2 >5 NA D555 INACTIVE >5 NA A241 INACTIVE SJ000288210-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288211-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288216-2 >5 NA B141 INACTIVE >5 NA C555 INACTIVE SJ000288219-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288224-2 >5 NA C555 INACTIVE >5 NA D555 INACTIVE SJ000288226-2 >5 NA C555 INACTIVE >5 NA B242 INACTIVE SJ000288238-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288244-2 0.1045 0.0914 - 0.1194 A213 MED 0.1311 0.0021 - 8.2851 A214 MED SJ000288246-2 >5 NA NB141 INACTIVE >5 NA D555 INACTIVE SJ000288249-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288262-2 >5 NA C555 INACTIVE 4.0527 NA C555 WEAK Differential activity within experimental error SJ000288270-2 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288274-2 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288278-2 0.0149 0.0104 - 0.0214 B110 HIGH 0.0159 0.0113 - 0.0225 B110 HIGH SJ000288284-2 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288304-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288306-1 0.306 0.1694 - 0.5530 A211 MED 0.171 0.0776 - 0.3768 A211 MED SJ000288308-1 >5 NA B341 INACTIVE >5 NA B344 INACTIVE SJ000288312-1 >5 NA D555 INACTIVE >5 NA C555 INACTIVE SJ000288313-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288316-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288318-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288320-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000288325-1 >5 NA B333 INACTIVE 4.198 4.0769 - 4.3227 B313 WEAK Differential activity within experimental error SJ000288326-1 >5 NA A241 INACTIVE >5 NA B341 INACTIVE SJ000288327-1 >5 NA D555 INACTIVE >5 NA D555 INACTIVE SJ000288328-1 >5 NA C555 INACTIVE >5 NA C555 INACTIVE SJ000518967-1 0.3177 0.2999-0.3357 A212 MED 0.3133 0.2964-0.3311 A212 MED DIHYDROARTEMISININ SJ000518972-1 0.3581 0.3459-0.3639 A212 MED 0.3311 0.3206-0.3428 A212 MED ARTESUNATE sample ATC_L1 ATC_L2 ATC_L3 ATC_L4 SJ000000250-8 C Cardiovascular system C01 Cardiac therapy C01B Antiarrhythmics, class I and III C01BC Antiarrhythmics, class Ic SJ000000854-6 V Various V99 Unassigned V99M Natural products V99ME Flavone SJ000113084-4 C Cardiovascular system C02 Antihypertensives C02C Antiadrenergic agents, peripherally acting C02CA Alpha-adrenoreceptor antagonists SJ000126662-3 V Various V99 Unassigned V99N Neurotransmitter V99NU Purinergic agonist SJ000285182-2 V Various V99 Unassigned V99N Neurotransmitter V99NJ GABA antagonist SJ000285183-2B Blood and bloodB05 forming Blood organs;#Dsubstitued Dermatologicalsand perfusion solutions;#D08;#R Respiratory AB05C ntisepticssystem Irrigating and disinfectants;#D09 solutions;#D08A Antiseptics MedicatedB05CA Antiinfectives;#D08AJand dressin disinfectants;#D09Ags;#R02 Throat Quaternary preparations Medicated ammonium dressings;#R02A compounds;#D09AA Throat preparations Medicated dressings with antiinfectives;#R02AA Antiseptics SJ000285185-4 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01B Antimalarials P01BA Aminoquinolines SJ000285188-6 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285190-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285193-1 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01A Alkylating agents L01AA Nitrogen mustard analogues SJ000285194-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01A Alkylating agents L01AA Nitrogen mustard analogues SJ000285194-4 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01A Alkylating agents L01AA Nitrogen mustard analogues SJ000285195-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BB Purine analogues SJ000285196-2 L Antineoplastic and immunomodulating agentsL01 Antineoplastics agents;#L04 ImmunosuppressantsL01B Antimetabolites;#L04A ImmunosuppressantsL01BA Folic acid analogues;#L04AX Other immunosuppressants SJ000285197-1 L Antineoplastic and immunomodulating agents L04 Immunosuppressants L04A Immunosuppressants L04AA Selective immunosuppressants SJ000285200-6 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01C Agents against leishmaniasis and trypanosomiasP01CX Other isagents against leishmaniasis and trypanosomiasis SJ000285202-2 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01A Agents against amoebiasis and otherP01AX protozoal Other diseases agents against amoebiasis and other protozoal diseases SJ000285203-5 V Various V99 Unassigned V99S Oxidative phosphorylation V99SA Respiratory chain inhibitors SJ000285206-2 V Various V99 Unassigned V99A Agricultural/Industrial V99AG Rodenticide SJ000285207-1 D Dermatologicals D08 Antiseptics and disinfectants D08A Antiseptics and disinfectants D08AK Mercurial products SJ000285208-3 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BB Purine analogues SJ000285210-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01A Alkylating agents L01AA Nitrogen mustard analogues SJ000285212-1 V Various V99 Unassigned V99W Protein synthesis inhibitors V99WA Other SJ000285215-1 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01A Agents against amoebiasis and otherP01AX protozoal Other diseases agents against amoebiasis and other protozoal diseases SJ000285215-6 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01A Agents against amoebiasis and otherP01AX protozoal Other diseases agents against amoebiasis and other protozoal diseases SJ000285218-5 V Various V99 Unassigned V99U Phosphatase V99UB PPA2/PP1 SJ000285219-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285219-5 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285220-5 V Various V99 Unassigned V99M Natural products V99ML Terpene SJ000285221-4 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BA Folic acid analogues SJ000285225-2 V Various V99 Unassigned V99S Oxidative phosphorylation V99SA Respiratory chain inhibitors SJ000285226-6 J Antiinfectives for systemic use J05 Antivirals for systemic useJ05AF J05A Nucleoside Direct acting and antivi nucleotideral drugs reverse transcriptase inhibitors;#J05AR Antivirals for treatment of HIV infections, combinations SJ000285227-1 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285228-4 V Various V99 Unassigned V99W Protein synthesis inhibitors V99WA Other SJ000285229-2 V Various V99 Unassigned V99R Other V99RA Various SJ000285231-2 V Various V99 Unassigned V99S Oxidative phosphorylation V99SD Transport inhibitors SJ000285232-1 D Dermatologicals D06 Antibiotics and chemotherapeutics for dermatologicalD06B use Chemotherapeutics for topical use D06BB Antivirals SJ000285232-8 D Dermatologicals D06 Antibiotics and chemotherapeutics for dermatologicalD06B use Chemotherapeutics for topical use D06BB Antivirals SJ000285234-2 V Various V99 Unassigned V99J Ion V99JE Ionophore SJ000285235-3 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01C Plant alkaloids and other natural products L01CB Podophyllotoxin derivatives SJ000285238-3 M Musculo-skeletal system M04 Antigout preparations M04A Antigout preparations M04AC Preparations with no effect on uric acid metabolism SJ000285241-3 L Antineoplastic and immunomodulating agents L04 Immunosuppressants L04A Immunosuppressants L04AX Other immunosuppressants SJ000285242-3 D Dermatologicals;#R Respiratory systeD08m Antiseptics and disinfectants;#R02 ThroatD08A prepa Antisepticsrations and disinfectants;#R02A ThroatD08AJ pre Quaternaryparations ammonium compounds;#R02AA Antiseptics SJ000285243-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01D Cytotoxic antibiotics and related substances L01DC Other cytotoxic antibiotics SJ000285244-3 R Respiratory system R02 Throat preparations R02A Throat preparations R02AB Antibiotics SJ000285246-2 R Respiratory system R02 Throat preparations R02A Throat preparations R02AA Antiseptics SJ000285249-1 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01D Cytotoxic antibiotics and related substances L01DA Actinomycines SJ000285256-3 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01D Cytotoxic antibiotics and related substancesL01DB Anthracyclines and related substances SJ000285261-3 V Various V99 Unassigned V99H Dermatological V99HA Antiseptic A AlimentaryA01 Stomatological tractSJ000285262-1 and metabolism;#G preparations;#A07 Genito-urinary Antidiarrheals systemA01A ,Stomatological andintestinal sex hormones;#J anti-inflammatory/anti-infective preparations;#A07A Antiinfectives Intestinal for syst agentemic anti-infectives;#G01As;#G01 use Gynecological Antiinfectives anti-infectivesA01AB Anti-infectives and and antiseptics antiseptic and, excludingantisepticss;#J02 Antimycotics combinations for local ora forl with treatment;#A07AAsystemic corticosteroids;#J02A use Antibiotics;#G01AA Antimycotics Antibiotics;# for systemicJ02AA use Antibiotics SJ000285263-2 V Various V99 Unassigned V99A Agricultural/Industrial V99AA Disinfectant SJ000285267-3 P Antiparasitic products, insecticides,P03 and Ectoparasiticides, repellents including scabicides, insecticides, andP03A repellents Ectoparasiticides, including scabicides P03AA Sulphur containing products SJ000285270-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01A Alkylating agents L01AC Ethylene imines SJ000285272-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285273-3 D Dermatologicals D08 Antiseptics and disinfectants D08A Antiseptics and disinfectants D08AE Phenol and derivatives SJ000285276-2 V Various V99 Unassigned V99C Antimicrobial V99CA Antimicrobial SJ000285278-1 V Various V99 Unassigned V99G Cytoskeletal V99GB Inhibitors microtubule polymerization SJ000285279-2 N Nervous system N07 Other nervous system drugs N07A Parasympathomimetics N07AA Anticholinesterases SJ000285285-3 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01X Other antineoplastic agents L01XX Other antineoplastic agents SJ000285292-10 J Antiinfectives for systemic use J04 Antimycobacterials J04A Drugs for treatment of tuberculosis J04AB Antibiotics SJ000285294-1 D Dermatologicals D09 Medicated dressings D09A Medicated dressings D09AA Medicated dressings with antiinfectives SJ000285299-2 D Dermatologicals D06 Antibiotics and chemotherapeutics for dermatologicalD06B use Chemotherapeutics for topical use D06BB Antivirals SJ000285307-3 V Various V99 Unassigned V99C Antimicrobial V99CA Antimicrobial DSJ000285308-1 Dermatologicals;#G Genito-urinaryD08 systemAntiseptics and andsex hormones;#Rdisinfectants;#G01D08A Antiseptics Respiratory Gynecologica and system disinfectants;#G01Al anti-infectives and Antiinfect antiseptics;#R02ives and antiseptics, Throat prepa excludingrationsD08AH combinations Quinoline derivatives;#G01AC with corticosteroids;#R02A Quinoline Throatderiva tives;#R02AApreparations Antiseptics SJ000285313-3 V Various V99 Unassigned V99M Natural products V99MF Lipid SJ000285315-2 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01B Antimetabolites L01BC Pyrimidine analogues SJ000285316-4 J Antiinfectives for systemic use J01 Antibacterials for systemic use J01F Macrolides, lincosamides and streptogramins J01FF Lincosamides A Alimentary tract SJ000285317-2and metabolism;#DA01 DermatologicalStomatologicals;#G preparations;#D08 Genito-urinaryA01A Stomatological Antisepticssystem and preparations;#D08A an sexd disinfectants;#G01 hormones;#R Antiseptics Resp Gynecologicaliratory and system disinfectants;#G01A anti-infectivesA01AB Anti-infectives and Antiinfectives antiseptics;#R02 and antiseptics and antisept Throat for ics,localpreparations excluding oral treatment;#D08AH combinations with Quinoline corticosteroids;#R derivatives;#G01AC02A Throat Qui preparationsnoline derivatives;#R02AA Antiseptics SJ000285318-7 S Sensory organics;#V VariousS01 Ophthalmologicals;#V03 All otherS01E therapeutics Antiglaucoma products preparations and miotics;#V03A All otherS01EB therapeutic Parasympathomimetics;#V03AB products Antidotes A01 StomatologicalA preparations;#B05 Alimentary tract and Blood metabolism;#BSJ000285319-1 substitued andBlood perfusion andA01A bloo solutions;#D08 dStomatological forming organs;#D Antiseptics preparations;#B05CA01AB Dermatologicals;#R Anti-infectives and disinfectants;#D09 Irrigating and Respiratory antiseptics solutions;#D08A Medicated system;#S for local dressings;#R02 Antiseptics ora Sensoryl treatment;#B05CA organicsand Throat disinfectants;#D09A pre Antiinfectives;#D08ACparations;#S01 Medicated Ophthalmologicals;#S02 Biguanidesdressings;#R02A and amidines;#D09AA ThroatOtologicals;# preparations;#S01AS03 Medicated Ophthalmological dressingsAnti-infectives;#S02A and with otological antiinfectives;#R02AA preparationsAnti-infectives;#S03A Antiseptics;#S01AX Anti-infectives Other anti-infectives;#S02AA Anti-infectives;#S03AA Anti-infectives SJ000285321-4 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01D Cytotoxic antibiotics and related substancesL01DB Anthracyclines and related substances SJ000285323-3 V Various V99 Unassigned V99H Dermatological V99HA Antiseptic SJ000285327-1 V Various V99 Unassigned V99M Natural products V99MA Alkaloid SJ000285332-1 D Dermatologicals D11 ther dermatological preparations D11A Other dermatological preparations D11AX Other dermatologicals SJ000285334-4 J Antiinfectives for systemic use J01 Antibacterials for systemic use J01F Macrolides, lincosamides and streptogramins J01FA Macrolides SJ000285335-1 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01C Plant alkaloids and other natural products L01CA Vinca alkaloids and analogues SJ000285335-4 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01C Plant alkaloids and other natural products L01CA Vinca alkaloids and analogues SJ000285337-5 D Dermatologicals D10 Anti-acneD10A prepara Anti-acnetions preparations for topical use;#D10BD10AD Anti-acne Retinoids preparations for topical for systemicuse in acne;#D10BA use Retinoids for treatment of acne SJ000285337-8D Dermatologicals;#L Antineoplastic and immunomodulD10 atingAnti-acne agents preparations;#L01 D10AAntineoplastics Anti-acne agepreparationsnts for topical use;#L01XD10AD Other Retinoids antineoplastic for topical agents use in acne;#L01XX Other antineoplastic agents A01 StomatologicalA preparations;#B05 Alimentary tract and Blood metabolism;#BSJ000285338-3 substitued andBlood perfusion andA01A bloo solutions;#D08 dStomatological forming organs;#D Antiseptics preparations;#B05CA01AB Dermatologicals;#R Anti-infectives and disinfectants;#D09 Irrigating and Respiratory antiseptics solutions;#D08A Medicated system;#S for local dressings;#R02 Antiseptics ora Sensoryl treatment;#B05CA organicsand Throat disinfectants;#D09A pre Antiinfectives;#D08ACparations;#S01 Medicated Ophthalmologicals;#S02 Biguanidesdressings;#R02A and amidines;#D09AA ThroatOtologicals;# preparations;#S01AS03 Medicated Ophthalmological dressingsAnti-infectives;#S02A and with otological antiinfectives;#R02AA preparationsAnti-infectives;#S03A Antiseptics;#S01AX Anti-infectives Other anti-infectives;#S02AA Anti-infectives;#S03AA Anti-infectives SJ000285343-2 A Alimentary tract and metabolismA07 Antidiarrheals, intestinal anti-inflammatory/anti-infective agentsA07A Intestinal anti-infectives A07AB Sulfonamides A01 Stomatological Apreparations;#A07 Alimentary tract andAntidiarrheals metabolism;#C, intestinal Cardiovascular anti-inflammatory/anti-infective system;#DSJ000285358-5 Dermatologicals;#H agents;#C05 Systemics Vasoprotectives;#D07 hormonal pr eparationsCorticosteroids, combinationsCorticosteroids, (excluding with moderately dermat antibiotics;#D07X sexological hormones potent, preparations;#H02 combinations and Corticosteroids insulins);#R with Corticosteroids ,Respiratory antiseptics;#D07XAother combinations;#H02A system;#S for syst Corticosteroids,emic Sensory use;#R01Corticosteroids organics weak,Nasal forotherpreparations;#S01 syst combinations;#H02ABemic use, plain;#R01A Ophthalmologi Glucocorticoids;#R01AD Decongestantsc and other Cortico nasalsteroids;#S01BA preparations for topicalCorticosteroids, use;#S01B plain;#S01BB Anti-inflammato Cortirycosteroids agents;#S01C and mydriatics Anti-inflammatory in combination;#S01CA agents and anti-i Corn t SJ000285363-5 N Nervous system N05 Psycholeptics N05A Antipsychotics N05AH Diazepines, oxazepines, thiazepines and oxepines SJ000285364-2 C Cardiovascular system C08 Calcium channel blockersC08D Selective calcium channel blockers with direct cardiac C08DBeffects Benzothiazepine derivatives SJ000285365-1 V Various V99 Unassigned V99J Ion V99JE Ionophore SJ000285368-3 V Various V99 Unassigned V99M Natural products V99MJ Steroid SJ000285369-1 V Various V99 Unassigned V99A Agricultural/Industrial V99AA Disinfectant SJ000285373-9 A Alimentary tract and metabolism;#SA03 Sensory Drugs fororgani functionalA03Bcs Belladonna gastrointestinal and derivatives, disorders ;#S01plain;#A03C OphthalmologicalsA03BA Antisp Belladonnaasmodics alkaloids, in combination tertiary amines;#A03CBwith psycholeptics;#S01F Belladonna My anddriatics derivatives and cycloplegics in combination with psycholeptics;#S01FA Anticholinergics SJ000285375-2 N Nervous system N06 Psychoanaleptics N06A Antidepressants N06AX Other antidepressants SJ000285382-3 V Various V99 Unassigned V99M Natural products V99MJ Steroid SJ000285383-1 R Respiratory system R06 Antihistamines for systemic use R06A Antihistamines for systemic use R06AX Other antihistamines for systemic use SJ000285387-8 R Respiratory system R01 Nasal preparations R01B Nasal decongestants for systemic use R01BA Sympathomimetics SJ000285396-2 V Various V99 Unassigned V99N Neurotransmitter V99NX Serotonin antagonist SJ000285400-2 V Various V99 Unassigned V99C Antimicrobial V99CA Antimicrobial SJ000285410-5 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01X Other antineoplastic agents L01XX Other antineoplastic agents SJ000285413-1 V Various V99 Unassigned V99M Natural products V99MF Lipid SJ000285423-2 V Various V99 Unassigned V99L Lipase V99LA Monoacylglycerol lipase SJ000285426-2 V Various V99 Unassigned V99R Other V99RA Various SJ000285431-2 P Antiparasitic products, insecticides,P03 and Ectoparasiticides, repellents including scabicides, insecticides, andP03A repellents Ectoparasiticides, including scabicidesP03AX Other ectoparasiticides, including scabicides SJ000285433-1 B Blood and blood forming organs B01 Antithrombotic agents B01A Antithrombotic agents B01AC Platelet aggregation inhibitors excluding heparin SJ000285436-3 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01B Antimalarials P01BE Artemisinin and derivatives, plain SJ000285439-2D Dermatologicals;#RD06 Respiratory Antibiotics system;#S and chemotherapeutics Sensory organics for dermatological use;#R02D06A Antibiotics Throat preparations;#S01 for topical use;#R02A Ophthalmolo ThroatD06AX gicalspreparations;#S01A Other antibiotics Anti-infectives for topical use;#R02AB Antibiotics;#S01AA Antibiotics SJ000285440-2 V Various V99 Unassigned V99M Natural products V99MH Quinone SJ000285442-1 V Various V99 Unassigned V99D Antioxidant V99DA Antioxidant SJ000285443-2 V Various V99 Unassigned V99A Agricultural/Industrial V99AB Dye SJ000285445-2 V Various V99 Unassigned V99O Nuclear hormore receptor V99OI TR antagonist SJ000285450-2 D Dermatologicals D08 Antiseptics and disinfectants D08A Antiseptics and disinfectants D08AA Acridine derivatives SJ000285451-3 V Various V99 Unassigned V99M Natural products V99MA Alkaloid A07 Antidiarrheals,SJ000285452-1A Alimentary intestinal tract and anti-inflammatory/an metabolism;#DA07E Intestinal Dermatologicalti-infective anti-inflammatory agents;#D07s;#R Respiratory agents;#D07A Corticosteroids, system Cort dermatoloicosteroids,gical plain;#R01A preparations;#R01 DecongestantsA07EA Nasal Corticosteroids preparations;#R03 and other actingnasal preparationslocally;#D07AC Drugs for obstructive for Corticotopical airway steroids,use;#R03B diseases potent Other (group drugs III);#R01AD for obstructive Corticosteroids airway diseases,;#R03BA inhalants Glucocorticoids A07 Antidiarrheals,SJ000285452-5A Alimentary intestinal tract and anti-inflammatory/an metabolism;#DA07E Intestinal Dermatologicalti-infective anti-inflammatory agents;#D07s;#R Respiratory agents;#D07A Corticosteroids, system Cort dermatoloicosteroids,gical plain;#R01A preparations;#R01 DecongestantsA07EA Nasal Corticosteroids preparations;#R03 and other actingnasal preparationslocally;#D07AC Drugs for obstructive for Corticotopical airway steroids,use;#R03B diseases potent Other (group drugs III);#R01AD for obstructive Corticosteroids airway diseases,;#R03BA inhalants Glucocorticoids SJ000285453-3 C Cardiovascular system C03 Diuretics C03D Potassium-sparing agents C03DA Aldosterone antagonists SJ000285454-2 J Antiinfectives for systemic use J01 Antibacterials for systemic use J01D Other beta-lactam antibacterials J01DB First-generation cephalosporins SJ000285460-1 J Antiinfectives for systemic use J01 Antibacterials for systemic use J01M Quinolone antibacterials J01MB Other quinolones SJ000285461-1 A Alimentary tract and metabolism A03 Drugs for functional gastrointestinal disordersA03A Drugs for functional bowel disordersA03AA Synthetic anticholinergics, esters with tertiary amino group SJ000285462-2 D Dermatologicals D10 Anti-acne preparations D10A Anti-acne preparations for topical use D10AF Anti-infectives for treatment of acne SJ000285465-2 N Nervous system N06 Psychoanaleptics N06D Anti-dementia drugs N06DX Other anti-dementia drugs SJ000285466-4 N Nervous system N03 Antiepileptics N03A Antiepileptics N03AG Fatty acid derivatives SJ000285484-2 C Cardiovascular system C01 Cardiac therapy C01C Cardiac stimulants excluding cardiac glycosideC01CAs Adrenergic and dopaminergic agents SJ000285487-3 C Cardiovascular system;#R RespiratoryC03 system Diuretics;#R03C03B Drugs Low-ceiling for obstructive diuretics, airway excluding diseases thiazides;#R03D Other systemic drugsC03BD for obstructive Xanthine airwayderivatives;#R03DA diseases Xanthines SJ000285490-1 V Various V99 Unassigned V99M Natural products V99MM Xanthanoid SJ000285502-5 C Cardiovascular system C01 Cardiac therapy C01B Antiarrhythmics, class I and III C01BD Antiarrhythmics, class III SJ000285504-2 N Nervous system N01 Anesthetics N01B Anesthetics, local N01BB Amides SJ000285506-2 V Various V99 Unassigned V99R Other V99RA Various SJ000285508-1 L Antineoplastic and immunomodulating agents L01 Antineoplastics agents L01C Plant alkaloids and other natural products L01CD Taxanes SJ000285512-1 V Various V99 Unassigned V99M Natural products V99ML Terpene A AlimentarySJ000285522-3 tractA08 A08A Antiobesityand metabolism;#C Antiobesity preparation,A08AA preparations, Cardiovascular Centrally excluding excluding acting diet system;#R antiobesityproduct diet produs;#C01 Respiratory products;#C01CActs;#C01C Cardiac system;#S therapy;#R01Cardiac Adrenergic stimulantsSensory Nasal andorganics excluding preparations;#R03 dopaminergic cardiac agents;#R01AA glyc Drugsosides;#R01A for obstructive Sympathom Decongestants airwayimetics, diseases;#S01 and plain;#R01AB other nasal Ophthal Sympathomimetics,preparatmologicalsions for topical combination use;#R03Cs excluding Adrenergics corticosteroids;#R03CA for systemic use;#S01F Alpha- Mydriatics and beta- andadrenoreceptor cycloplegics agonists;#S01FB Sympathomimetics excl SJ000285526-3 V Various V99 Unassigned V99N Neurotransmitter V99NK GABA reuptake inhibitor SJ000285536-1 N Nervous system;#S Sensory organicsN07 Other nervous system drugs;#S01N07A Ophthalmologica Parasympathomimetics;#S01Els AntiglaucomaN07AX prepar Otherations parasympathomimetics;#S01EB and miotics Parasympathomimetics SJ000285540-4 C Cardiovascular system C02 AntihyperteC02C Antiadrenergicnsives agents, peripherally acting;#C0C02CA2L Alpha-adrenoreceptor Antihypertensives and antagonists;#C02LE diuretics in combination Alpha-adrenoreceptor antagonists and diuretics A01 Stomatological preparations;#A07A Alimentary Antidiarrheals tract and, intestinal metabolism;#C anti-inflammatory/anti-infective Cardiovascular system;#D agentSJ000285541-3 Dermatologicals;#Hs;#C05 Vasoprotectives;#D07 Systemics hormonal Corticosteroids, preparations dermat (excludingological preparations;#H02 sex hormonescombinations and Corticosteroids insulins);#R with antibiotics;#D07X Respiratory for systemic system;#S use;#R01 Corticosteroids Sensory Nasal preparations;#S01 ,organics;#V other combinations;#H02A Variousntibiotics;#D07XA Ophthalmologi Corticosteroids c Corticosteroids, for syst weak,emic other use, combplain;#R01Ainations;#H02AB Decongestants Glucocorticoids;#R01AD and other nasal preparations Corticostero forids;#S01BA topical use;#S01B Corticosteroids, Anti-inflammato plain;#S01BBry agents;#S01C Corticoste Anti-inflammatoryroids and mydriatics agents in combination;#S01CB and anti-in Corticosteroids/anti-infectives/mydriatics in combination;#S A01 Stomatological preparations;#A07A Alimentary Antidiarrheals tract and, intestinal metabolism;#C anti-inflammatory/anti-infective Cardiovascular system;#D agentSJ000285542-2 Dermatologicals;#Hs;#C05 Vasoprotectives;#D07 Systemics hormonal Corticosteroids, preparations dermat (excludingological preparations;#H02 sex hormonescombinations and Corticosteroids insulins);#R with antibiotics;#D07X Respiratory for systemic system;#S use;#R01 Corticosteroids Sensory Nasal preparations;#S01 ,organics;#V other combinations;#H02A Variousntibiotics;#D07XA Ophthalmologi Corticosteroids c Corticosteroids, for syst weak,emic other use, combplain;#R01Ainations;#H02AB Decongestants Glucocorticoids;#R01AD and other nasal preparations Corticostero forids;#S01BA topical use;#S01B Corticosteroids, Anti-inflammato plain;#S01BBry agents;#S01C Corticoste Anti-inflammatoryroids and mydriatics agents in combination;#S01CB and anti-in Corticosteroids/anti-infectives/mydriatics in combination;#S A AlimentarySJ000285543-1 tract and metabolism;#H SystemicsA07 horm Antidiarrheals,onal preparations intestinal (excluding anti-inflammatory/an sex hormonesti-infective andA07E insul ins) agents;#H02Intestinal anti-inflammatory Corticosteroids agents;#H02A for systemic use CorticosteroidsA07EA for Corticosteroids systemic use, acting plain locally;#H02AB Glucocorticoids SJ000285544-3 P Antiparasitic products, insecticides, and repellents P01 Antiprotozoals P01B Antimalarials P01BA Aminoquinolines SJ000285547-5 C Cardiovascular system C01 Cardiac therapy C01B Antiarrhythmics, class I and III C01BA Antiarrhythmics, class Ia SJ000285549-5 N Nervous system N05 Psycholeptics N05A Antipsychotics N05AB Phenothiazines with piperazine structure SJ000285551-2 G Genito-urinary system and sex hormonG03es Sex hormones and modulators ofG03D the genital Progestogens;#G03F system ProgestogensG03DA and Pregnen-(4) estrogens derivatives;#G03FA in combination Progestogens and estrogens, fixed combinations SJ000285554-2 V Various V99 Unassigned V99M Natural products V99ME Flavone SJ000285564-2 N Nervous system N06 Psychoanaleptics N06A Antidepressants N06AF Monoamine oxidase inhibitors, non-selective SJ000285569-2 P Antiparasitic products, insecticides, and repellents P02 Antihelmintics P02C Antinematodal agents P02CB Piperazine and derivatives SJ000285572-3M Musculo-skeletal system;#P Antiparasitic M09products Other, insecticides, drugs for disorders and repellents of the musculo-skeletM09A Otheral system;#P01 drugs for disorders Antiprotozoals of the musculo-skeletal system;#P01BM09AA Quinine Antimalarials and derivatives;#P01BC Methanolquinolines SJ000285572-4M Musculo-skeletal system;#P Antiparasitic M09products Other, insecticides, drugs for disorders and repellents of the musculo-skeletM09A Otheral system;#P01 drugs for disorders Antiprotozoals of the musculo-skeletal system;#P01BM09AA Quinine Antimalarials and derivatives;#P01BC Methanolquinolines SJ000285574-1 V Various V99 Unassigned V99H Dermatological V99HC Local anesthetic SJ000285577-2 C Cardiovascular system C03 Diuretics C03D Potassium-sparing agents C03DA Aldosterone antagonists SJ000285584-1 V Various V99 Unassigned V99K Kinase V99KC CK2 inhibitor SJ000285586-2 G Genito-urinary system and sex hormonG03es Sex hormones and modulators of the genital system G03B Androgens G03BB 5-androstanon-(3) derivatives SJ000285587-1 V Various V99 Unassigned V99M Natural products V99MM Xanthanoid SJ000285588-1 V Various V99 Unassigned V99M Natural products V99ME Flavone SJ000285591-1 M Musculo-skeletalM01 Anti-inflammatory system;#S and Sensory antirheumaticsM01A organics Anti-inflammatory products;#M02 and Topical antirheumatic products forproducts, jointM01AA and non-steroids;#M02A muscular Butylpyrazolidines;#M02AA pain;#S01 Topical Ophthalmologicals products Anti-inflammatory for joint and p mreparations,uscular pain;#S01B non-steroids Anti-inflammatory for topical use;#S01BC agents Anti-inflammatory agents, non-steroids SJ000285592-5 L Antineoplastic and immunomodulating agents L02 Endocrine therapy L02B Hormone antagonists and related agents L02BA Anti-estrogens