bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Activity of epigenetic inhibitors against Babesia divergens.

Leen N. Vanheer1,#, Björn F.C. Kafsack1,*

1 Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY, USA # current affiliation: London Interdisciplinary Doctoral Programme (LIDo) * please address correspondence to [email protected]

ABSTRACT

Babesiosis in a tick-borne parasitic disease of humans and livestock, that has dramatically increased in frequency and geographical range over the past few decades. Infection of cattle often causes large economic losses, and human infection can be fatal in immunocompromised patients. Unlike for malaria, another disease caused by hemoprotozoan parasites, limited treatment options exist for Babesia infections. As epigenetic regulation is a promising target for new anti-parasitic drugs, we screened 324 epigenetic inhibitors against Babesia divergens blood stages and identified 75 (23%) and 17 (5%) compounds that displayed ≥90% inhibition at 10 µM and 1 µM, respectively, including over a dozen compounds with activity in the low nanomolar range. We observed differential activity of some inhibitor classes against Babesia divergens and Plasmodium falciparum parasites and identified pairs of compounds with a high difference in activity, despite a high similarity in chemical structure, highlighting new insights into the development of epigenetic inhibitors as anti-parasitic drugs.

INTRODUCTION

Babesiosis is an emerging parasitic disease caused by the intra-erythrocytic Babesia parasite and has many clinical features similar to malaria infection. Babesia infections in cattle are widespread and lead to economic losses through death, reduction in meat and milk yield, and the cost of control measures. More than 100 Babesia species have been identified but only a few infect humans. However, human babesiosis is an increasing concern worldwide, as the number of reported cases have increased over the last decades and the geographical rage of transmission has expanded 1,2. In Europe, Babesia divergens is responsible for most human babesiosis cases 3. In the US, the majority of human Babesia infections is caused by Babesia microti, although cases of B. divergens-like organisms have been reported as well 4. Transmission occurs through the bite of an infected tick or occasionally through blood transfusion, which has prompted the screening of the blood supply for Babesia parasites in an increasing number of U.S. states 5 . Symptomatic human babesiosis is manifested by malaria- like symptoms, such as fever and general malaise. Treatment recommendations for human

1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. babesiosis are a combination of atovaquone and azithromycin for mild to moderate babesiosis and clindamycin plus quinine for severe infection 6. However, for immunocompromised patients, cases of treatment failure for both regimens have been reported 7,8 and babesiosis can lead to organ failure and death. Asplenic patients, in particular, are at high risk for relapsing infections and require long antimicrobial treatment 9. Recently, tafenoquine, a newly FDA- approved drug for malaria treatment, showed activity against Babesia microti in mice but further studies are needed 10. As treatment options for relapsing Babesia infection are limited, research into new drugs for babesiosis is critical.

In eukaryotes, epigenetic regulation of gene expression, mediated by small modifications of nucleosomes and on DNA itself, has been found to be critical for cellular homeostasis and differentiation 11. In a recent screen of 324 commercially available epigenetic inhibitors against Plasmodium falciparum 12, we showed that 54 compounds exhibited ≥50% inhibition at 1 µM in vitro, suggesting that the epigenetic machinery could be a promising novel drug target. Since Plasmodium and Babesia are related parasite species with similarly complex life cycles that share much of the epigenetic regulatory machinery, we decided to determine the activity of these epigenetic inhibitors against Babesia divergens, for which an in vitro culture system and drug assays are established.

METHODS

Commercially available libraries of 324 epigenetic inhibitors from Selleckchem (Houston, TX) and Cayman Chemicals (Ann Arbor, MI) were purchased. Libraries were aliquoted and diluted in DMSO to 2 mM and 0.2 mM in V-bottom 96-well plate and stored at -80°C.

Babesia divergens (Bd Rouen 1987 strain 13) was grown in vitro in human A+ RBC at low parasitemia. Cultures were flushed with 90% nitrogen, 5% oxygen and 5% carbon dioxide and cultured at 37°C. SYBR Green based growth assays were used to determine in vitro activity of the epigenetic inhibitors against B. divergens 14,15. Briefly, flat-bottom 96-well plates at a total of 200 μL per well and 0.5% DMSO, at a final 5% hematocrit, 0.5% parasitemia for B. divergens were incubated at 37°C for 72 hours and thereafter frozen at -80°C. Upon thawing, 100 μL of SYBR Green (ThermoFisher) diluted in lysis buffer (0.2 μL 10,000X SYBR Green per mL lysis buffer) was added to each well and plates were shaken in the dark at room temperature for 1 hour. Fluorescence was then measured using a Molecular Devices SpectraMax ID5 plate reader. Values were normalized to solvent-treated controls (included in triplicate on each plate). EC50 values were calculated using the nlmLS function of the minpack.lm package (v1.2-1) of the R statistical package (v3.6.0).

2 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Protein sequences of histone modifying enzymes were retrieved from PlasmoDB and PiroplasmaDB 16,17. Orthologs were identified using annotated ortholog groups as well as reciprocal BLAST searches. NCBI Conserved Domain Search 18 was used to identify conserved protein domains. Protein sequences were aligned using MUSCLE 19 and visualized using MView 20. In cases where two consecutive genes were identified as orthologs, the geneID for the ortholog containing the catalytic domain was indicated as the ortholog.

Structural feature (SkelSphere) analysis and Activity Cliff Analysis were performed using Osiris DataWarrior v5.2.1, at 80% chemical structure similarity cut-off. Structure-Activity Landscape Index (SALI) values 21 were calculated as:

SALI I,J = ((|Ai − Aj|) ⁄ (1 − sim(i, j))) in which Ai and Aj are the activities of compounds i and j, and sim(I,j) is the similarity coefficient between the two molecules.

RESULTS AND DISCUSSION

Evolutionary conservation of epigenetic modifying enzymes in piroplasmid parasites. Among eukaryotes, the most common epigenetic modifications are acetylation of histone lysine residues, methylation of histone lysine and arginine residues, and methylation of deoxycytidine on DNA. We were able to identify orthologs for most of the enzymes classes that place and remove these marks in the genomes of piroplasmid parasites, which includes Babesia and Theileria species (Figure 1, Supplemental Table 1, Supplemental Dataset 1). Orthologs to seven of the eleven Su(var)3-9/Enhancer of Zeste/Trithorax (SET)-domain-containing lysine- specific histone methyltransferases (KMT) present in P. falciparum could be identified in at least one piroplasmid genome. Orthologs of PfSET4 and PfSET5 were absent in the entire clade while an ortholog to PfSET6 could only be identified in B. microti. Orthologs to PfSET9 could be identified in all piroplasmida genomes but are missing key residues within the catalytic SET domain thus making it unlikely that these have retained methyltransferase activity. Most piroplasmid genomes also retain two additional trithorax-like SET-domain proteins found in other apicomplexan parasites that were lost in malaria parasites. Histone demethylases were notably reduced compared to P. falciparum, with B. divergens and B. bovis only encoding a single member of the Jumonji and LSD demethylase families.

All three the histone arginine methyltransferases (RMTs) in P. falciparum had orthologs in B. divergens, but the PRTM3 ortholog was lost outside the Babesia sensu stricto clade (represented by B. bovis and B. divergens). Histone acetyltransferases (HATs) and

3 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. deacetylases (HDACs) were generally conserved between malaria parasites and the piroplasmida. Notable is the absence of Sir2A from all piroplasmid genomes and loss of HAT1 from the Babesia sensu stricto clade. An ortholog of a proposed Cytosine-5 DNA methyltransferase in Plasmodium falciparum 22 is present in Theileria equi but could not be identified in the other genomes examined.

Activity of epigenetic inhibitors against Babesia divergens. Given these differences in histone modifying enzymes between P. falciparum and the piroplasms, we decided to test the susceptibility of B. divergens to a library of epigenetic inhibitors previously screened against P. falciparum 12. Of the 324 compounds tested, 125 (39%) showed ≥50% inhibition at 10 µM against B. divergens blood stages, of which 46 (14%) retained greater than half-maximal activity at 1 µM (Figure 2A, Supplemental Figure 1 and Table 2, Supplemental Dataset 2). 75 (23%) and 17 (5%) of compounds exhibited greater than 90% inhibition at 10 µM and 1 µM, respectively. Dose-response curves were performed for 17 compounds with sub-micromolar EC90 values (Figure 2B). Of these, the HDAC inhibitors quisinostat and apicidin were the most potent compounds, with EC50 values as low as 5 - 6 nM. These top hits included two FDA-approved drugs mitomycin C and panobinostat with EC50 values of 63 nM and 27 nM, respectively. Peak plasma concentration of panobinostat dosage indicated for treatment of multiple myeloma only correspond to EC75 for Babesia making it an unlikely candidate for treatment 23,24. Mitomycin C is a CpG DNA crosslinking agent indicated, indicated for gastric and pancreatic adenocarcinoma treatment and was recently also approved for low-grade upper tract urothelial cancer.25. Intravenous administration during chemotherapy leads to plasma concentration of 5 µM 26, around 20-fold higher than its EC90 value against B. divergens. We previously determined toxicity of selected compounds against human HepG2 cells 12. Several compounds displayed only moderate toxicity against HepG2 cells even at 1 µM (Figure 2B). This drug screen identifies promising compounds for additional SAR studies for possible use as a new class of anti-Babesia drugs.

Differential activity of epigenetic inhibitors against B. divergens and P. falciparum. Next, we compared these results to our recently completed screen of this library against P. falciparum blood stages 12. A similar number of compounds had >50% inhibition at 1 µM against both species (46 against B. divergens compared to 54 against P. falciparum). For both species, compounds targeting histone methylation, deacteylation, demethylation or phosphorylation were the most active, while compounds targeting histone acetylation, PARPylation, histone reader domains, DNA methylation or other pathways had little to no activity (Supplemental Table 1).

4 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Twenty-five compounds with >50% inhibition at 1 µM against one species exhibited greater than two-fold difference in activity in the other (Figure 3). HDAC inhibitors were generally less active against B. divergens than against P. falciparum, with 18% of the 85 HDAC inhibitors in the library showing ≥90% inhibition at 1 µM against P. falciparum versus only 8% for B. divergens (Supplemental Table) 2. Interestingly, several HDAC inhibitors with high differential activity target the human HDAC1 (class I) or HDAC6 (class IIb), suggesting that the HDACs may be more divergent from the human enzymes in B. divergens than in P. falciparum. An additional 25 compounds exhibited greater than 75% inhibition against both P. falciparum and B. divergens. Thirteen of these were HDAC inhibitors many of which have activity against multiple HDAC classes. Surprisingly, of the 15 HMT inhibitors in Figure 3B, the four compounds with greater activity against B. divergens target either ethery the H3K79 HMT DOT1L or the H3K27 HMT EZH1/2 in humans, orthologs to which are absent from both species. As in our previous study, the DNMT inhibitor SGI-1027 was also among the most active compounds against B. divergens, despite no identifiable DNMT ortholog in Babesia species and PfDNMT being dispensable for asexual growth 27, suggesting that SGI-1027 likely has one or more alternative targets.

Similarity and activity cliff analysis of activity against B. divergens and P. falciparum. Structural feature analysis of all 324 unique compounds revealed five clusters of four compounds or more with >80% structural similarity (Supplemental Figure 2), including seven HDAC inhibitors with a common hydroxamate-based scaffold, seven HMT inhibitors sharing a common diaminoquinazoline backbone (Figure 5) and three HMT inhibitors an 1H-indazole-4- carboxamide scaffold (Figure 4B). Activity Cliff analysis identifies pairs with high differential activity, despite high structural similarity. Delta activity and SALI values are plotted for all pairs of the library in Supplemental Figure 3. Compound pairs of interest have >50% delta activity and >80% structural similarity (Figure 4A). Twelve pairs were activity cliffs in both P. falciparum and B. divergens, while three only had more than 50% delta activity in B. divergens and 4 only in P. falciparum.

The HMT inhibitor UNC1999 displays an activity cliff for activity against B. divergens when paired with GK343 and GSK503, despite the former having 91% structural similarity (Figure 4B). Interestingly, the IC50 values for mammalian EZH2 enzyme inhibition are similar for all three compounds, while UNC1999 is the only compound with potent EZH1 inhibition as well. Kinase inhibitors belinostat and oxamflatin show activity cliffs for both species (Figure 4C). Additional structural comparisons of the remaining activity cliff pairs can be found in

5 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Supplemental Figure 4. These activity cliff pairs provide insight into the structural features that confer activity against P. falciparum and B. divergens.

Differential HMT inhibitors with a diaminoquinazoline backbone.

Seven HMT inhibitors of the SET3 HMT G9a share a diaminoquinazoline backbone 28-33. Figure 5A shows pairs with >60% similarity and >50% delta activity at 1 µM in both species. For Babesia divergens, the side group on position 4 of the diaminoquinazoline scaffold seemed to have the most effect on compound activity (Figure 5B). A cyclohexylmethyl-4-piperidylamine side group (UNC0631) showed the highest activity, while the EC50 value increased 5-6 times when changing to a cyclohexyl-4-piperidylamine (UNC0646) or 1-benzyl-4-piperidylamine (BIX01294) side group. Substituting the ring structure with an isopropyl group (UNC0638 and UNC0642) further decreased the remaining activity by half. Activity is completely lost when the side group consists of a lone 4-piperidylamine (UNC0224).

Previous SAR studies of diaminoquinazolines methyltransferase inhibitors have been performed for P. falciparum, 34,35. We confirmed that substituting the 1-benzyl-4-piperidylamine of BIX01294 on position 4 of the diaminoquinazoline scaffold with a cyclohexylmethyl-4- piperidylamine (UNC0631) or a cyclohexyl-4-piperidylamine (UNC0646) reduced the activity against P. falciparum (Supplemental Figure 5). However, in disagreement with previous findings, the substitution with a 1-isopropyl-4-piperidylamine (UNC0642 and UNC0638) did not impact the activity against P. falciparum.

It was previously reported that a lysine mimetic side group on position 7 of the diaminoquinazoline scaffold lacks activity against P. falciparum, despite exhibiting potent activity against G9a due to interactions in the lysine binding channel of this enzyme. We confirmed that a dimethylpropylamine side group (UNC0224) loses activity as previously reported, but interestingly, we found the lysine mimetic side groups 1-propylpyrrolidine (UNC0642 and UNC0638) and 1-propylpiperidine (UNC0631 and UNC0646) retained most of their activity. This suggests that compounds with a lysine mimetic side group on position 7 of the diaminoquinazoline scaffold can inhibit P. falciparum only if combined with certain side groups on position 2 and 4 of the scaffold.

Three of the diaminoquinazoline compounds have a high differential activity against both species, showing 17-24 times more activity against P. falciparum (Figure 5C). As two of these compounds (UNC0642 and UNC0638) share a 1-isopropyl-4-piperidylamine group on position 4 and a 1-propylpyrrolidine group on position 7, these might contribute to this difference in

6 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. activity. As the closest related P. falciparum HMT to HsG9a is PfSET3, it is possible that the binding site on the HMT enzyme for these three compounds is more divergent from HsG9a in BdSET3 than in PfSET3.

Overall, we show that epigenetic enzymes may be a promising novel target in Babesia divergens. Our library of 324 epigenetic inhibitors includes 19 pairs of compounds with high delta activity despite high structural similarity, which provide insight into the structural features that confer activity against P. falciparum and B. divergens. Multiple diaminoquinazoline backbone HMT inhibitors show highly active against both species tested, with UNC0631 displaying a low nanomolar range EC50 value against both P. falciparum and B. divergens, while UNC0224 is inactive against both species despite minor structural differences with the active diaminoquinazoline compounds.

ACKNOWLEDGEMENTS: We thank the High Throughput and Spectroscopy Resource Center at Rockefeller University for technical assistance, and Elisabeth Martinez (UT Southwestern) for additional JIB-04 inhibitor. We also thank Laura Kirkman for providing the B. divergens strain and valuable feedback on the manuscript. This work was supported by a Bohmfalk Charitable Trust Research Grant and NIH 1R01AI141965 and 1R01AI138499 to BK, and a Belgian American Educational Foundation post-doctoral fellowship to LV.

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9 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. FIGURE LEGENDS

Figure 1. Conservation of epigenetic writer and eraser enzymes orthologs among the Piroplasmida with P. falciparum as an outgroup.

Figure 2. Activity of epigenetic inhibitors against Babesia divergens. (A) 125 compounds with ≥50% inhibition at 10 µM. Heatmap of mean percent inhibition at 10 and 1 µM compared to solvent-treated controls (n=3). Compounds are grouped based on the reported epigenetic process affected in higher eukaryotes: Histone deacetylation (HDAC), histone acetylation (HAT), histone methylation (HMT), Histone Demethylases (HDM), DNA methylation (DNMT), and “Other”. (B) Dose response analysis for 17 compounds with sub-micromolar EC50 values (n=2), with corresponding HepG2 inhibition at 1 µM.

Figure 3. Differential activity of epigenetic inhibitors against B. divergens and P. falciparum. (A) Scatterplot comparing %inhibition at 1 µM against B. divergens and P. falciparum. Dotted lines indicate more than 2-fold difference in activity. Compound names are for compounds with more than 2-fold difference in activity and more than 50% inhibition at 1 µM against one species. An enlarged scatterplot with labelled compound names is displayed for compounds with ≥75% at 1 µM against both species. (B) Heatmap of compounds with at least 50% inhibition at 1 µM against one species, ordered by the delta activity (% Pf inhibition - % Bd inhibition) and grouped by target category.

Figure 4. Activity cliff analysis. (A) Scatterplot of activity cliff pairs with >50% delta activity and >80% structural similarity (SALI), grouped by species. (B-C) Examples of activity cliff pairs with chemical structures and activity.

Figure 5. Compounds with diaminoquinazoline backbone. (A) Compounds with >60% similarity and >50% delta activity at 1 µM. (B) Activity of compounds with diaminoquinazoline backbone against Babesia divergens. (C) Changes in chemical structure that confer differential activity against both species.

10 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. SUPPLEMENTARY FIGURE LEGENDS

Supplemental Figure 1: Mean percent inhibition of all 324 compounds against B. divergens at 10 μM and 1 μM. The dotted and dashed lines indicate 50% and 90% inhibition, respectively. Compounds are ordered by increasing activity at 10 μM. Error bars are standard error of n=3.

Supplemental Figure 2: Structural feature similarity landscape. Compounds with >80% structural similarity were grouped in Datawarrior (SkelSphere). Color indicates reported epigenetic process targeted in higher eukaryotes.

Supplemental Figure 3: Activity cliff analysis for Babesia divergens at 1 μM. Scatterplot with each dot representing a pair of compounds in the library. Compound pairs of interest have >50% delta activity (dashed line) and >80% structural similarity (dotted line).

Supplemental Figure 4: Structural representation of the remaining activity cliff pairs that are displayed in figure 4A.

Supplemental Figure 5: Activity of compounds with diaminoquinazoline backbone against P. falciparum.

Supplemental Table 1: EC50 Activity of epigenetic inhibitors tested grouped by target category. Percentage of active compounds is indicated in brackets (n=2-3).

Supplemental Table 2: EC90 Activity of epigenetic inhibitors tested grouped by target category. Percentage of active compounds is indicated in brackets (n=2-3).

Supplemental Dataset 1: Gene identifiers of epigenetic writer and reader enzyme orthologs in Figure 1.

Supplemental Dataset 2: Mean percent inhibition of all compounds against B. divergens at 10 μM and 1 μM.

11 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.04.411777; this version posted December 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license.

Writers Erasers

PfSET1 X PfJmjC1 PfSET2 PfJmjC2 X X PfSET3 X HKDM PfJmj3 / / / / / / PfSET4 / / / / / / PfLSD1 PfSET5 / / / / / / PfLSD2 / / / / / / PfSET6 KMT X X X X X PfSET7 PfHDAC1 PfSET8 PfHDA1 PfSET9 HDAC PfHDA2 X PfSET10 PfSir2A / / / / / / LSMT-like PfSir2B ATRX2-like / TRX-like / X

PfPRMT1 HRMT PfPRMT5 PfPRMT3 X X X X

PfGCN5 Ortholog present PfMYST HAT Ortholog with degenerated catalytic domain PfHAT1 X X PfELP3 X Ortholog lost DNMT PfDNMT X X X X X / No ortholog identified

Figure 1. Evolutionary conservation of epigenetic modifying enzymes in piroplasmid parasites. Comparison of epigenetic modifying enzyme orthologs between P. falciparum, B. microti, T. equi, T. annulata, C. felix, B. bovis and B. microti, with a representation of the evolutionary relationship between these species. Babesia Babesia SGI−1027 DNMT Gemcitabine SGI−1027 Babesia Babesia DNMT Babesia Gemcitabine Babesia Babesia CAY10603 SGI−1027 SGI−1027 BabesiaQuisinostat DNMT Gemcitabine DNMT SGI−1027 DacinostatSGISGI−−10271027 Quisinostat DNMT Gemcitabine DNMT SGIAbexinostat−1027 PanobinostatSGI−1027 Gemcitabine DNMT GemcitabineGemcitabine DNMT SGI−1027 CAY10603 AR−42 DacinostatGemcitabine CAY10603 QuisinostatCAY10603 Apicidin Dacinostat DacinostatQuisinostat Quisinostat Trichostatin A Panobinostat PanobinostatDacinostat TrichostatinQuisinostat A Abexinostat Abexinostat PanobinostatTrichostatin A AR−42Panobinostat AR−42 Dacinostat DacinostatAbexinostat Panobinostat AR−42 DacinostatGivinostat HC ToxinDacinostat Quisinostat QuisinostatApicidin ApicidinHCAR Toxin−42 CUDC−101 Trichostatin A Quisinostat AbexinostatApicidin Panobinostat Panobinostat TrichostatinBelinostat A AbexinostatTrichostatin A Trichostatin A AR−42 ARApicidinPanobinostat−42 PracinostatTrichostatin A Trichostatin A GivinostatAR−42 Givinostat GivinostatHC Toxin HCPracinostatTrichostatin Toxin A Givinostat CUDC−101 VorinostatCUDCGivinostat−101 BelinostatHC Toxin HC Toxin HC Toxin CUDC−101 CAY10603CUDC−101 Belinostat Abexinostat AbexinostatTenovinHC Toxin−6 CAY10603CUDC−101 BelinostatPracinostat OxamflatinBelinostat VorinostatAbexinostat Apicidin ApicidinPracinostat Pracinostat CAY10398 Givinostat CUDCApicidin−101 CAY10398Pracinostat Pracinostat BabesiaPracinostat GivinostatNexturastat A Coumarin−SAHA Babesia Belinostat HDAC Babesia Pracinostat Givinostat Vorinostat Vorinostat Babesia BelinostatCoumarin−SAHA NexturastatBelinostat A Babesia CAY10603SGI−1027 CAY10603Vorinostat HDAC M 344Belinostat SGI−Tenovin1027 −6 DNMT TenovinGemcitabine−6 SGICAY10603CAY10398−1027 M 344 CAY10603 DNMT Oxamflatin Vorinostat DNMT VorinostatTenovin−6 Pyroxamide Gemcitabine DNMT OxamflatinSGI−1027 Gemcitabine4−iodo−SAHA Vorinostat CUDC−101 DNMT CUDCGemcitabineCAY10398CAY10603−101 CAY10398ScriptaidOxamflatin 4−iodoiodo−SAHA CoumarinDacinostat−SAHA QuisinostatCUDC−101 LMK−235CAY10398 CAY10603Nexturastat A Nexturastat A CoumarinResminostat−SAHA Coumarin−SAHA HDAC HDAC QuisinostatNexturastatAbexinostat A PanobinostatNexturastatMNexturastat 344 A A NullscriptCoumarin−SAHA DacinostatCoumarin−SAHA HDAC CoumarinQuisinostat−SAHA HDACHDAC Dacinostat ScriptaidNexturastat A AbexinostatCAY10398 PanobinostatMAR 344−42 MPyroxamideCoumarin 344 −SAHA HDAC CAY10398PyroxamideQuisinostat ApicidinRicolinostatCAY10398 ResminostatM 344 AR−442−iodo−SAHA 4Dacinostat−iodo−SAHA TrichostatinPyroxamide A Ricolinostat Babesia 4Panobinostat−iodoiodo−SAHA 4LMK4−−iodoiodoiodo−235−−SAHASAHA Pyroxamide QuisinostatScriptaid Babesia ScriptaidApicidinTrichostatin A ARCBHA−42 Thiomyristoyl4−iodoiodo−SAHA SGIResminostat−1027 TrichostatinLMKGivinostat−235 A HCLMKScriptaid Toxin−235 Mocetinostat DNMT Panobinostat ResminostatSGINullscript−1027 ThiomyristoylResminostat LMK−235 GemcitabineM 344 DNMT MAR 344SGI−42HC− 1027Toxin CUDCNullscript−101 Babesia CBHA Trichostatin A GemcitabineScriptaid AbexinostatM 344 Nullscript GivinostatPyroxamide PyroxamideHC ToxinBelinostat ScriptaidMocetinostat TenovinSGI−1027−6 CAY10603 ResminostatApicidin PracinostatPyroxamide DNMT OxamflatinScriptaid HC ToxinRicolinostat RicolinostatCUDCQuisinostat−101 ResminostatCitarinostat GemcitabineResminostat Dacinostat QuisinostatRicolinostatPracinostat GivinostatRicolinostatSRT1720Ricolinostat Citarinostat BelinostatLMK−235 LMKAbexinostatPanobinostat−235 Belinostat TubastatinRicolinostat A AbexinostatCBHA PracinostatThiomyristoylVorinostat ThiomyristoylTubastatinLMK−235 A Quisinostat ApicidinAR−42 CBHAPracinostatDacinostatMocetinostatTenovin−6 CAY10603 SRT1720PanobinostatThiomyristoyl Thiomyristoyl Givinostat VorinostatMocetinostatSRT2104CBHA PracinostatQuisinostat Babesia ThiomyristoylApicidinCBHAOxamflatin SRT2104DacinostatMocetinostat Nullscript Belinostat Babesia CAY10398CBHAThiomyristoyl Apicidin VorinostatPanobinostat NullscriptTrichostatinTenovinCUDC−−1016 A JIBNullscript−04 Babesia CBHA Mocetinostat MocetinostatCAY10603ARSGINexturastat−42−1027 A CoumarinTenovinSP2509SGI−1027−6SAHA JIBTrichostatin−04Tenovin A −6 bioRxivTenovin preprintTrichostatin−6 doi: A https://doi.org/10.1101/2020.12.04.411777DNMTHDAC Oxamflatin DNMTHDM; this version NexturastatpostedOxamflatinMocetinostat DecemberA 4, 2020. The SP2509ARcopyright−42SGI−1027 holder for this OxamflatinGivinostatCitarinostat CitarinostatVorinostatHCGemcitabineCoumarin Toxin −SAHA HDAC ML324Gemcitabine HDMDNMT Oxamflatin preprint (whichSRT1720 was not certified by peer review)CitarinostatCAY10398 is the author/funder, who hasMCitarinostatGSK Citarinostat344 granted−J4 bioRxiv a license toGSK HCdisplay Toxin−J4Gemcitabine the preprint in CUDCHC− 101Toxin SRT1720CAY10398CUDCTubastatin−101 A Pyroxamide ML324CUDCCitarinostat−101 Tubastatin A TubastatinCoumarinAbexinostatQuisinostat4−iodo− −ASAHASAHA TubastatinQuisinostatSRT1720 A NexturastatBelinostat A perpetuity. It is madeSRT1720PanobinostatScriptaid available under aCC-BY-NC4SRT1720UNC0379−Tubastatiniodoiodo 4.0−SAHA International A license. AbexinostatTubastatinQuisinostat A HDAC SRT2104 SRT2104NexturastatPracinostat A LMKPanobinostat−235 UNC0631PracinostatSRT1720 CoumarinApicidin−SAHA HDAC SRT2104DacinostatResminostat SRT2104BIX01294DacinostatSRT2104 SRT1720Panobinostat M 344Givinostat NullscriptUNC1999 UNC0646GivinostatSRT2104Dacinostat CAY10398PracinostatJIB−04 ApicidinM 344 Apicidin UNC0638 Vorinostat JIBPyroxamideBelinostat−JIB04Pyroxamide−04 ScriptaidUNC0631JIB−04 BelinostatApicidin 4−iodoSP2509−SAHA SP2509Trichostatin A ResminostatJIBTrichostatin−04 A BIX01294CAY10603 HDM Tenovin−6 HDM 4−iodoCAY10603iodoSP2509ARRicolinostat−−42SAHA SP2509LLYSP2509−507 JIBTrichostatin−04 A ScriptaidML324 HDM ML324 HDMHDM RicolinostatUNC0642AR−42 SGC0946VorinostatSP2509 Oxamflatin LMKVorinostatGSKHCLMK−235 Toxin−−J4235 GSKML324−J4 HDM UNC0642AR−42 ResminostatGSK−J4 GSKCAY10398CBHA−J4 ThiomyristoylUNC0646HC Toxin CAY10398GSK−J4 CUDC−101 NullscriptML324CUDC−101 MocetinostatML324GSK−J4 UNC1999CoumarinHC− ToxinSAHA M 344 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SRT1720EPZ005687 CUDCEPZ005687PyroxamideBRD4770−101 Chaetocin SRT2104 EPZ004777SRT1720PanobinostatMocetinostatNeplanocin4UNC0379−iodo−SAHA A AbexinostatMI−136 EI1TenovinEPZ005687Pyroxamide−6 ThiomyristoylEtoposide SRT2104 UNC0631Neplanocin4EPZ004777−iodo−SAHA A EI1Oxamflatin Babesia EtoposideSRT2104DacinostatCBHAGSK503LMKBIX01294−235 PracinostatMILMK−463−235 GSK343Neplanocin4−iodo−SAHA A NullscriptEPZ005687 Apicidin UNC0646GivinostatGSK503GSK343Etoposide CitarinostatLMK−235 JIB−Mocetinostat04 EPZ005687TenovinLLYNullscriptUNC1999−507−6 LLYNullscript−507 MI−3 GSK503 GSK126 DNMT JIBTrichostatinSGI−04UNC0631−1027 A Babesia UNC0638BelinostatALLYEPZ005687−366−507 EtoposideTubastatinLLYNullscript −A507 SP2509Citarinostat GSK126OxamflatinGemcitabinePinometostatScriptaid BIX01294PinometostatScriptaidGSK126 EtoposideSRT1720LLY−507 Babesia HDMHMT Sinefungin SP2509AR−LLY42 −507 SGICAY10603MIPinometostat−−21027 MI−136PinometostatScriptaid ML324SRT1720 HMTHDMHMT SinefunginCitarinostatMIResminostat−2 HMTDNMT Babesia SGC0946VorinostatMIResminostat−2 SRT2104Pinometostat Babesia Chaetocin GSKHC ToxinUNC0642−J4 HMTHMT GemcitabineMISinefungin−−32 HMT MI−nc MIResminostat−2 SGI−1027 GSKTubastatin−J4 A ChaetocinTubastatinQuisinostatARicolinostat−196 A UNC0642CAY10398AUNC0224RicolinostatChaetocin−196 HMT MI−2 DNMT EI1 EI1ML324CUDCSRT1720PanobinostatThiomyristoylUNC0646−101 SGIQuisinostatUNC1999−1027 AJIB−366−04ARicolinostat−196 Gemcitabine SGISRT2104−1027 MIUNC0638−463 DNMTDNMT GemcitabineUNC1999CoumarinMIPinometostatThiomyristoylEI1−463 −SAHA Sinefungin DNMT UNC0379GSK503 GSK503AbexinostatSRT2104DacinostatMocetinostat PanobinostatEPZ004777Nexturastat A HDM SinefunginSP2509MIThiomyristoyl−463 Gemcitabine UNC0631BRD4770SGC0946 HDAC BRD4770NeplanocinMocetinostatGSK503 A HDM UNC0224GSK−J4 BIX01294A−196 APracinostat−196ApicidinCBHA QuisinostatDacinostatUNC0379M 344 BRD4770Mocetinostat CAY10603 JIB−04 UNC0646ChaetocinBRD4770 ApicidinChaetocinMICBHAA−nc196 GSK126ML324 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AbexinostatMGSK126SGI 344−1776 AbexinostatBelinostatSGIChaetocinCBHAScriptaidReversineUNC1999−Apicidin1776 GSK126ML324CYC116UNC1999 ChaetocinBI−847325 CAY10398 MI−PracinostatCAY10603136 CAY10603TenovinPinometostatReversinePanobinostatTrichostatin−6 A Kinase NullscriptThiomyristoylReversineAbexinostatBelinostatSGI−1776 Kinase DecernotinibEI1 UNC1999 HMT PyroxamideSinefunginSNS−314 HMT PracinostatSNSEI1MIResminostatZMEPZ004777Dacinostat−Gandotinib−3142 447439 ScriptaidMocetinostatUNC0631BisindolylmaleimideEPZ004777CAY10603 IXKinaseKinase TG101209Reversine 4−iodo−SAHA MI−GivinostatVorinostat463 HMT VorinostatOxamflatinMIZMUNC0379AR−2− 44743942 LestaurtinibZMPracinostatSNS 447439−314 TG101209GSK343EPZ004777 4ChaetocinGo−iodoiodo 6983−SAHA GivinostatGoGSK343ARicolinostat 6983CXApicidinHC−Hesperadin196− Toxin6258 ResminostatCBHAAuroraUNC0646FedratinibUNC0379Vorinostat A Inhibitor I FedratinibMI−3 ZM 447439 Scriptaid GSK343BelinostatCAY10398 CAY10398CitarinostatAEPZ005687−196 TenovinCXGivinostatGo− 62586983−6 UNC0379 Resminostat CoumarinLMKEI1Reversine−235−SAHA BelinostatReversineMI−MIThiomyristoylGandotinib3TrichostatinCUDCAZ−463 960−101 A RicolinostatSNSUNC0638TG101209EPZ005687BelinostatCAY10398−314 WHIEtoposide−P154CX−6258 Babesia CAY10603 CoumarinTubastatinNeplanocinARCX−−42−6258SAHA A A OxamflatinGandotinibReversine EPZ005687 A−366NexturastatNullscriptGSK503Aurora A Inhibitor A I CAY10603AuroraEtoposideBRD4770MocetinostatAZAbexinostat 960A Inhibitor I ThiomyristoylGoBIX01294PacritinibNeplanocinCAY10603Coumarin 6983 −SAHA A AT9283MI−136Gandotinib M 344 HDAC Vorinostat HDAC VorinostatNexturastatEtoposideSRT1720BRD4770AZGSK503HCPracinostatBI −960Toxin847325 A MocetinostatCitarinostatSGC0946AZMomelotinibAurora 960 A Inhibitor I Neplanocin A Pyroxamide SGIMI−−MScriptaid21027AENMD −344196−2076 MENMDMI 344−ChaetocinCBHABMS136−2076−911543 HDAC TubastatinHesperadinGSK503VorinostatNexturastat A A DanusertibMI−nc AZ 960 DNMT Babesia CAY10398MI−136 CAY10398SRT2104TenovinLLYCUDCGivinostatLestaurtinib−507−−1016 CBHABIUNC0642BMSHTHMENMD− 847325344−−01911543−0152076 PacritinibA−366GSK503 Ricolinostat GemcitabineMI−PyroxamideResminostat3NVP−BSK805 PyroxamideNVPMI−EI1GSK1070916ncAbexinostatBelinostat−BSK805 SRT1720BIGSK1070916LLYCAY10398−847325−507 PacritinibBMS−911543 Coumarin4MI−iodo−463−SAHA−SAHA CoumarinOxamflatinPinometostatSGI−−1776SAHA TenovinSRT2104ReversineUNC1999BarasertibGSK1070916PinometostatPyroxamideNVP−BSK8056 TozasertibSinefunginGSK1070916LLY−507 LMK−235 SGIUNC0224−NexturastatRicolinostat1027BMS−911543 A 4BMSA−JIBiodo−GSK343366−MomelotinibPracinostatCAY10603SNS−04−911543SAHA−314 OxamflatinEPZ004777MomelotinibCoumarin−SAHA GSK1070916Pinometostat DNMTHDAC QuisinostatPinometostatLMKGSK343−235 HMT NexturastatLMKCitarinostat−MIVorinostat235−2 A HMT ZMWHIMomelotinibMI4BMS− −iodo4474392−P154−−911543SAHA ENMDUNC0224−Momelotinib2076 CBHA DNMTHDAC GemcitabineMThiomyristoylWZ4003 344 HDACHDAC WZ4003SinefunginSP2509MIBisindolylmaleimideGivinostatGo−3 6983 IX CitarinostatJIBCXUNC0379BisindolylmaleimideTozasertibNexturastatLMK−625804−235 A IX HMT EnzastaurinGSK126MomelotinibMI−2 BabesiaPanobinostatNeplanocinNullscriptMocetinostatAZM−366 447439 A HDM MNullscript 344TubastatinABelinostatCAY10398−196 A HDACHDAC TubastatinSP2509CXEPZ005687BisindolylmaleimideAWZ4003−−1966258 A IX EnzastaurinBisindolylmaleimide IX Thiomyristoyl DacinostatPyroxamideScriptaid HDM PyroxamideZMUNC0224GSKEtoposide CYC116MI447439CoumarinReversine−−J4463 −SAHA HDM GandotinibCYC116AZD1480MNullscript 344 CEP−33779BisindolylmaleimideA−196 IX BabesiaQuisinostatMI−CBHAncMIGSK1070916−2 ScriptaidSRT1720CAY10603Aurora A Inhibitor I SRT1720GSKNeplanocinCYC116MIPyroxamideZM−−463 J4447439 A CEPLestaurtinib−33779CYC116 Nullscript A ApicidinSGI4Resminostat−iodo−1027−SAHA 4GSK1070916GSK126−ML324iodoMISGIBRD4770VorinostatNexturastat−−136SAHA−1776 A AZSGICEPScriptaid 960−−177633779 AZD1480CYC116MI−463 DNMT BabesiaPanobinostatTenovinMI−3 −6 HDAC ResminostatSRT2104MENMD 344 −2076 SRT2104ML324GSK503SGIBRD4770GSK1070916−1776 AuroraSGI A Inhibitor−1776 I Mocetinostat TrichostatinGemcitabineLMKRicolinostatSGIAT9283−−1027235 A LMKRicolinostatAT9283MI−BarasertibChaetocinCAY10398235−nc BMSBarasertibGo69764Resminostat−iodo−911543−SAHA Go6976SGIBRD4770−1776 DNMT DacinostatGandotinibOxamflatinUNC0224 PyroxamideNVP−BSK805 UNC0631GSK1070916LLYBarasertibChaetocinLMKAT9283−507−235 SNS−314Barasertib Citarinostat AR−42SGINullscriptThiomyristoylGemcitabineCYC116−1027 NullscriptThiomyristoylCYC116LestaurtinibUNC0631AJIBDecernotinibEI1Coumarin−366−04 −SAHA JIBGSK1070916PinometostatDecernotinibDanusertibRicolinostat−04 JNJ−7706621BarasertibChaetocin DNMTKinaseDNMT ApicidinHesperadinQuisinostatCitarinostatPinometostat KinaseKinase 4BMS−iodo−−911543SAHA Kinase UNC0646MomelotinibJNJDecernotinibEI1NullscriptThiomyristoylCYC116−7706621 NVPGo 6983−BSK805Decernotinib SRT1720 HC ToxinGemcitabinePanobinostatScriptaidMocetinostatBisindolylmaleimide IXKinase ScriptaidMocetinostatBisindolylmaleimideAuroraUNC0646SinefunginSP2509TG101209GSK343NexturastatLMK A− 235Inhibitor A I IXKinaseKinaseKinaseHMT SP2509MomelotinibMITG101209−2 Kinase NVPHesperadin−BSK805DecernotinibEI1 TrichostatinAZ 960CBHATubastatinQuisinostatNeplanocinFedratinib A A A HDMHDMHDACHDAC UNC0638UNC0224MWZ4003 344 HDM GSKUNC0638BisindolylmaleimideCerdulatinibTG101209GSK343ScriptaidMocetinostatBisindolylmaleimide−J4 IX IXKinaseKinase TAK−901TG101209 Tubastatin A CUDCDacinostatResminostat−101 ResminostatCBHAFedratinibSNSUNC0224GSKFedratinibMINullscriptZM−314−−3 447439J4 BIX01294AFedratinibMI−196−3 TAKBI−847325−901TG101209GSK343 ARAbexinostatCX−−42QuisinostatRicolinostatTenovinSRT1720PanobinostatMITG1012096258−nc −6 TenovinBIX01294GSK126ML324PyroxamideScriptaid−6 ML324CYC116MIKWResminostatCBHAFedratinib−463−2449 CerdulatinibFedratinibMI−3 SRT2104 Apicidin RicolinostatTG101209GoGSK126 WHIEtoposide6983GSK1070916−P154 SGC0946SGIWHIEtoposideTenovin−1776−P154−6 ReversineFedratinib HCPracinostatBI− Toxin847325PanobinostatTrichostatinThiomyristoylOxamflatinSRT2104DacinostatPacritinib A OxamflatinHesperadinSGC0946AT92834Resminostat−iodo−SAHA UNC0642SGIBRD4770TAKRicolinostatTG101209−−1776901 KWZM −4474392449WHIEtoposide−P154 DacinostatCitarinostatGandotinib ThiomyristoylPacritinibHesperadinUNC0631AT9283MILMKRicolinostatAT9283−136−235 UNC0631BarasertibChaetocinAT9283EnzastaurinMIOxamflatin−136 WZ4003 JIB−04 CUDCGivinostatLestaurtinibARMocetinostatApicidinMomelotinib−−10142 MocetinostatCitarinostatBIUNC0642−Lestaurtinib847325DanusertibCYC116 UNC0646UNC1999ThiomyristoylPacritinib WZ4003CX−6258AT9283MI−136 BelinostatApicidinTubastatinJIBHesperadin−04 A Kinase TubastatinMomelotinibBI−AuroraUNC0646847325DanusertibMINullscriptThiomyristoyl−nc A Inhibitor I Kinase EPZ004777DecernotinibEI1DanusertibDecernotinibMIMocetinostatCitarinostat−nc HTHGandotinib−01−015 SP2509 AbexinostatSGIHCCBHATrichostatin−HTH1776 Toxin−01−015 A CBHAReversineUNC1999AuroraPacritinibAScriptaidMocetinostatBisindolylmaleimide−366 A Inhibitor I IXKinaseKinase UNC0638TG101209TubastatinMomelotinib A DanusertibMI−nc HDM PracinostatCAY10603TrichostatinCUDCSRT1720SP2509ARAZ− 96042−101 A SRT1720HTHReversineSNSUNC0638Pacritinib−01−314−015 UNC0379TG101209GSK343PacritinibACBHAHTH−366−01−015 AZ 960 ML324 HDM SNSTenovinSRT2104Barasertib−314 −6 TenovinBarasertibZMEPZ004777SNS TozasertibSinefunginResminostatCBHA447439Fedratinib−−6314 BIX01294EPZ005687FedratinibMITozasertibPirarubicinSRT1720−3 MitomycinPacritinibA−366 C GivinostatVorinostatARAbexinostatOxamflatinGSKHCCX− −Toxin42−6258J4 SRT2104ZMGoBIX01294 TozasertibTenovin447439TG101209 6983−6 SGC0946TozasertibSinefunginTenovinBarasertib−6 BMS−911543Tozasertib GSK−J4 Go HC6983WHI Toxin−P154 OxamflatinWHICXUNC0379−ENMDUNC0224Ricolinostat−6258P154−2076 NeplanocinWHIEtoposideENMDMitomycinUNC0224SRT2104−P154−2076 AC PirarubicinGSK1070916TozasertibSinefungin BelinostatCAY10398PracinostatCitarinostatJIBML324CUDCBI−84732504−101 CXHesperadinSGC0946−ENMDThiomyristoylOxamflatinPacritinib6258 −2076 UNC0642GSK503AT9283G007ENMDOxamflatinWHI−−LK−P1542076 G007−ENMDLKUNC0224−2076 CoumarinReversineCUDCGivinostatLestaurtinibTozasertib−−SAHA101 CitarinostatJIBTozasertibGandotinibEPZ005687−UNC064204EnzastaurinGSK126Citarinostat AT9283MIEnzastaurinGSK126−136 G007Momelotinib−ENMDLK −2076 UNC0379 CAY10603TubastatinSP2509Abexinostat A SP2509GandotinibNeplanocinBIMocetinostatMomelotinib−847325 A UNC1999LLYDanusertibMIOFEnzastaurinCitarinostatJIBTozasertib−−nc−−507104 CPI−0610EnzastaurinGSK126 HDM NexturastatAuroraAbexinostatBelinostatUNC0631SGIAZD1480 A− 1776Inhibitor A I HDM TubastatinAZD1480AZUNC1999 CEP960CBHATubastatin− 33779A A EPZ004777PinometostatCEPSP2509−33779 BisindolylmaleimideEnzastaurin IX BIX01294 HDAC VorinostatSRT1720GSKPracinostat−J4 SRT1720GSKAZGSK503Reversine −Lestaurtinib960SRT1720HTHJ4 −01−015 HDM PacritinibAPFICEPTubastatin−AZD1480366−4−33779 A CPICYC116−637CEP−33779 MENMD 344PracinostatCAY10603UNC0646SNSCEP−2076−31433779 CEPBMSEPZ004777AZD1480Tenovin−Barasertib−33779911543−6 HMTHMT UNC0379MIAZD1480LestaurtinibSRT1720GSK−2 −J4 CEP−33779 UNC1999 CAY10398VorinostatSRT2104ML324Givinostat SRT2104ML324BMSLLYZMAuroraSRT2104−−507 447439911543 A Inhibitor I HMT TozasertibSinefunginBromosporineAZD1480AuroraCEP− 33779A Inhibitor I GSK6853SGI−1776AZD1480Lestaurtinib PyroxamideNVPGivinostatUNC0638BelinostatGoGo6976−BSK805 6983 Go6976GSK1070916UNC0379Go6976OxamflatinWHI−P154 EPZ005687AENMDUNC0224Go6976CPISRT2104ML324−196−637−2076 BromosporineAZD1480Aurora A Inhibitor I UNC0631 CoumarinCAY10398−SAHA GSK1070916PinometostatCXSNSCitarinostat−6258−314 NeplanocinMIENMDGo6976SNSGo6976−463−−3142076 A BromosporineBarasertibGo6976 4BMS−iodoBelinostatJIBUNC0631BIX01294CAY10603ReversineDanusertib−−911543−SAHA04 UNC0631DanusertibMomelotinibEPZ005687JNJJIBTozasertib−−047706621 EnzastaurinGSK126JNJI−BRD9−7706621 AZD5153Go6976SNS−314 LLY−507 NexturastatLMKCoumarinUNC0646−235 A −SAHA HMT JIBMomelotinibMI−Gandotinib−04GoTubastatinSP25092 6983 A GSK503BRD4770JNJGoUNC0631Danusertib 6983−7706621 Kinase AZD5153DecernotinibJNJ−7706621 HDAC WZ4003CAY10603SP2509SGC0946VorinostatAuroraJNJ−7706621 A Inhibitor I HDM UNC0646JNJBisindolylmaleimideNeplanocinNVP−AZD14807706621−BSK805 A IX ChaetocinCEPNVPGSK6853JIB−33779−04BSK805 PFITG101209−4 JNJGo 6983−7706621 UNC0642 HDACHDM MNullscript 344VorinostatNexturastatUNC0638 A SP2509BisindolylmaleimideA−AZ196HesperadinSRT1720GSK 960−J4 IX Other LLYLestaurtinibNVPHesperadinUNC0646JNJ−507−BSK8057706621 Other PFI−4 NVP−BSK805 HDAC ZM MGSKUNC0642CAY10398447439ENMDCerdulatinib 344−J4−2076 HDM UNC0638CerdulatinibGSK503TAKML324CEP−−90133779 EI1AZD1480TAKRVXSP2509−901208 Other OFFedratinib−1 NVPHesperadin−BSK805 UNC0646 PyroxamideScriptaidCAY10398BIX01294 GSKCYC116MIBMS−−BISRT2104463Go6976J4−847325−911543 HDM PinometostatAuroraTAKBIUNC0638Cerdulatinib−847325− 901A Inhibitor I TAK−901 GSK1070916PyroxamideML324UNC1999CoumarinNVPKW−−2449BSK805−SAHA BIX01294KWLLY−Cerdulatinib2449−507 HMT MIGSK343Go6976CerdulatinibCPIGSK−2−0610−J4 (+)WHI−JQ1−P154TAKBI−847325−901 UNC0638 4Resminostat−iodoCoumarinSGC0946−SAHA−SAHA ML324SGC0946SGIBRD4770GSK1070916CerdulatinibReversineUNC0631−Danusertib1776 MIJNJSNSCerdulatinibReversineBIX01294KW−3−−7706621314−2449 Cerdulatinib AT92834EPZ004777NexturastatBMSTAK−iodo−−901−911543SAHA A TAKPinometostatKWJIB−901−−042449 AJNJGoKWRucaparibML324SGC0946−196 6983−−77066212449 IIAT9283−BRD9CerdulatinibReversine SGC0946 HDAC LMKRicolinostatNexturastatUNC0631UNC0642−235 A HMT UNC0642BarasertibChaetocinMomelotinibMIZMSP2509UNC0646JNJ−2 447439−7706621 EtoposideNVPAZD5153KWZMTAK− −447439BSK8052449−901 RVXDanusertib−208KW−2449 HDACHDAC ThiomyristoylCYC116LMKUNC1999UNC0379MWZ4003Enzastaurin 344−235 HDM UNC0631EnzastaurinDecernotinibBisindolylmaleimideWZ4003CXUNC0638−6258 IX MIHesperadinWZ4003UNC0642−463136 RVX−208KWZM −4474392449 BRD4770 KinaseHDAC NullscriptMNullscriptUNC0646 344 UNC1999DecernotinibEI1BisindolylmaleimideAGSK−Cerdulatinib196−J4 IX BRD4770TAKBIPFWZ4003CXUNC0631Enzastaurin−847325−−−CBP19016258 PFPacritinib−CBP1WZ4003 MocetinostatBisindolylmaleimideEPZ004777EPZ005687PyroxamideZMDecernotinib 447439 IXKinaseKinaseKinase UNC0646EPZ004777DecernotinibCYC116HTHGandotinibBIX01294KW−−244901−015 MICerdulatinibHTHUNC1999−nc−01−015 WZ4003CX−6258 EPZ004777 ScriptaidPyroxamideScriptaidUNC0638 UNC0638TG101209GSK343CYC116MIML324SGC0946−463 ChaetocinCerdulatinibReversine(+)HTHGandotinibUNC0646EPZ004777Decernotinib−JQ1−01−015 AZ6102TozasertibHTH−01−015 ResminostatCBHAFedratinibUNC0379Neplanocin4GSK1070916−iodo−SAHA A UNC0379FedratinibSGIAZTAK− 9601776−901 AKWUNC0638−366−2449 RSCENMD−133−HTHGandotinib2076−01−015 Etoposide 4ResminostatBIX01294LMKPirarubicin−iodo−235−SAHA BIX01294FedratinibMI−SGIBRD4770MitomycinUNC0631UNC06423 −1776 C EI1SinefunginKWZMOTX015AZUNC0379 −447439 9602449 RSC−133 TenovinTG101209EPZ005687GSK503AT9283−6 EPZ005687PirarubicinBarasertibMitomycinBMSUNC1999Enzastaurin−911543 C WZ4003MitomycinBIX01294 C RucaparibEnzastaurinAZ 960 EPZ005687 RicolinostatLMKRicolinostatSGC0946NeplanocinNullscriptMitomycin−235 AC SGC0946WHIEtoposideBarasertibChaetocinPirarubicinUNC0646−P154 GSK343UNC0224CXRSCBMSEPZ005687Pirarubicin−6258−−133911543 RucaparibMitomycin C OxamflatinThiomyristoylLLYCYC116−507 NeplanocinMitomycinDecernotinibPirarubicinGSK1070916EPZ004777Decernotinib AC MIGSK126HTHGandotinibPirarubicinSGC0946−3−01−015 OTX015CEP−33779BMS−911543 GSK126 Kinase ThiomyristoylPacritinibNullscriptUNC0642GSK503ScriptaidG007−LK Kinase UNC0642AT9283MI−DecernotinibEI1G007UNC0638136 −LK AZ6102GSK1070916NeplanocinMitomycin AC OTX015Pirarubicin MocetinostatCitarinostatScriptaidMocetinostatPinometostatBisindolylmaleimide IXKinaseKinase GSK503G007TG101209G007MomelotinibUNC0379−LK−LK EtoposideAZG007MomelotinibUNC0642 960−LK AZD1480GSK1070916 HMT Sinefungin HMT TubastatinMomelotinibUNC1999LLYMIResminostatOF−−2−5071 A UNC1999LLYDanusertibMI−TG101209GSK343CPI507BIX01294EPZ005687ncPirarubicin−0610 10 1 LestaurtinibMitomycinCPIGSK503G007−0610−LK C 10 1 Go6976G007Momelotinib−LK HMT CBHAHTHResminostatCBHAEPZ004777MIFedratinib−01−2−015 OFFedratinibMI−CPIBisindolylmaleimideSGC09461−3−0610 IX MIPirarubicinBMSCPIBisindolylmaleimideUNC1999LLY−136−9115435070610 IX CPI−0610 Chaetocin SRT1720TenovinPinometostatARicolinostatPFI−196−4 −6 EPZ004777PinometostatPFIPacritinibA−366−CPINeplanocinMitomycin4 −637 AC concentration (µM)MIAuroraPirarubicinGSK1070916CPIOF−nc−−637 1A Inhibitor I concentration (µM)JNJ−7706621CPIBisindolylmaleimide−0610 IX EI1 HMT TenovinBarasertibRicolinostatUNC0379MITG101209−−26 TozasertibWHIEtoposideCYC116UNC0642GSK503G007−P154−LK SNSG007CPICYC116EPZ004777PinometostatPFI−−314−637LK4 NVP−BSK805CPI−637 HMT SRT2104OxamflatinMIThiomyristoylBromosporine−463 HMT UNC0379MIBromosporineTozasertibSinefungin−2GSK6853UNC1999 AG007MomelotinibGSK6853−366−LK CPICYC116−637 GSK503 OxamflatinWHIThiomyristoylEPZ005687APacritinib−−P154196 HMT A−196AT9283MIGSK6853SGILLYOF−136−−50711776 HMT GoCPIGSK6853SGIUNC0379MIBromosporine 6983−06102−1776 TAK−901GSK6853 MocetinostatCitarinostatBRD4770CPI−637 EPZ005687CPIENMDUNC0224Bromosporine−BarasertibEPZ004777Pinometostat637−2076 HMT SinefunginHesperadinBisindolylmaleimideBromosporineEPZ005687A−196 IX GSK6853SGI−1776 A−196 CitarinostatJIBTozasertib−04TubastatinNeplanocinMICBHAMomelotinib−463 A A NeplanocinMIEnzastaurinGSK126−Danusertib463MIPFI−nc−4 A UNC0224CPICYC116BromosporineBarasertibCPI−637−637 CerdulatinibBromosporine CBHABRD4770ChaetocinI−BRD9 HMT IEnzastaurin−BRD9AZD5153DecernotinibUNC0379MIBromosporine−2 BIGSK6853AZD5153NeplanocinMI−847325−463 A % inhibition BromosporineBarasertib MI−136 TubastatinSP2509SRT1720GSK503TenovinHTH− A01−6−015 KinaseHMT GSK503BRD4770PacritinibAEPZ005687A−−366196 % inhibition GSK126ReversineGSK6853SGIAZD5153DecernotinibI−−BRD91776 % inhibition KW−2449AZD5153 HDM AZD1480TenovinChaetocinEI1GSK6853−6 CEPPFITG101209CPI−33779−−4637 Kinase BromosporinePFIGSK503BRD4770−4 0 25 50 WZ400375 100AZD5153Decernotinib MI−463 Other SRT1720GSKCEPSRT2104LLY−OxamflatinBarasertib−J433779−507 OtherOther LLYChaetocinGSK6853Lestaurtinib−TozasertibSinefungin507NeplanocinMI−463 A Other 0 25 50ZMBromosporineBarasertibPFITG101209GSK685375 447439−1004 Kinase 0 25 50 75 100PFI−4 ML324OxamflatinEI1GSK343WHIRVX−P154208 Other EI1RVXAZD1480OFFedratinibBRD4770−I−208BRD9−1 OtherOther LestaurtinibAZD5153DecernotinibOFLLYChaetocin−−1507 Other HTH−01PFITG101209−015−4 GSK343 SRT2104PinometostatCitarinostat PinometostatAuroraENMDUNC0224GSK503 A− Inhibitor2076 I Kinase CXOFFedratinibEI1RVX−6258−1−208 OtherOther OF−1 Go6976CitarinostatJIBGSK343MICPI−−304−0610 GSK343CPIGo6976(+)−WHIChaetocinGSK68530610−JQ1−P154 Other AuroraGandotinibPFITG101209(+)Pinometostat−−4JQ1 A Inhibitor I OFFedratinib−1 Babesia A−366 HMT MITubastatinTozasertib−2 A HMT Other MISNS−Enzastaurin2GSK126LLY−314−507 OtherOther (+)WHIGSK343−JQ1−P154 Mitomycin(+)− CJQ1 JIBUNC0631Danusertib−04TubastatinSP2509MIEtoposideAZD1480Rucaparib−3 A MIRucaparibJNJ−3IIAT9283PinometostatEI1−−RVX7706621BRD9−208 OtherHMT SNSAZOFFedratinibIAT9283MI−CPI BRD9−960−1−2314−0610 (+)WHI−JQ1−P154 MI−2 HDM UNC0646AEtoposideSRT1720−196 AGo−196CEP 6983GSK343CPI−−337790610 GoBMS(+)WHIIMI−− BRD96983−JQ1−−3P154911543 PirarubicinIAT9283−BRD9 SGI−1027 SP2509JNJSRT1720GSKMI−CEPAZD51537706621−463136−−J433779 HMT EtoposideAZD5153NVPAZD1480LestaurtinibRVXDanusertibMI−BSK805−2−208 (+)RVXDanusertibARucaparib−196JQ1−208 I−BRD9 DNMT Babesia MI−3 HDM UNC0638ML324MISRT2104−136 MIHesperadin−463AZD1480MIRucaparib−3 HesperadinGSK1070916IIAT9283−RVXEtoposideBRD9−208 G007−RVXDanusertibLK −208 Gemcitabine GSKCerdulatinibSRT2104MI−PFJ4−nc−CBP1 MITAK−136AuroraPFPacritinibAEtoposide−−901196−CBP1 A Inhibitor I PFPacritinibMIAZD5153−463CBP1 CPI−0610RVX−208 UNC0224 BIX01294BRD4770MIGo6976−nc BRD4770PFBI−Go6976−847325PFMICBP1AZD5153−−463CBP1 BIMomelotinibRVXDanusertibPFMI−847325−−−136CBP1208 PFPacritinib−CBP1 SGI−1027 ML324KWA−JIB(+)2449−366−−04JQ1 MICerdulatinib−ncSNSAZ6102TozasertibMI−136−314 BisindolylmaleimideAZ6102TozasertibBRD4770PF−CBP1 IX CPI−637PF−CBP1 DNMT QuisinostatPinometostat SGC0946JIBUNC0631ChaetocinADanusertib−366−04 ChaetocinA(+)CerdulatinibReversine−366JNJ−AZ6102BRD4770JQ1PF−−7706621CBP1 ReversinePFPacritinibAZ6102MI−−CBP1nc AZ6102Tozasertib DNMT Gemcitabine TAKUNC0646EI1SinefunginSP2509−OTX015901 KWGoRSC−ENMDMI2449 −6983nc−133−2076 ZMCYC116AZ6102TozasertibRSCENMDChaetocinA(+)− 447439366−−JQ1133−2076 GSK6853AZ6102 Panobinostat HDM UNC0642SP2509SinefunginJNJ−7706621 EI1SinefunginOTX015KWZMNVP RSC−ChaetocinA447439(+)2449−366−JQ1BSK805−133 AZ6102RSC−133 ENMD−2076 Neplanocin A HDMHDM UNC0631EnzastaurinUNC0638GSK343UNC0224GSKRSC−−J4133 WZ4003HesperadinRucaparibEnzastaurin CXSGIRSCENMDRucaparibEnzastaurinEI1SinefunginOTX015−−6258−1776133−2076 BromosporineRSC−133 QuisinostatDacinostat UNC1999GSKUNC0224Cerdulatinib−J4 GSK343UNC0224RSCWZ4003CXTAK−RucaparibEI1Sinefungin−OTX0156258133−901 BarasertibRSCRucaparib−133 RucaparibEnzastaurin ApicidinMI−nc UNC0646DecernotinibBIX01294MIGSK126ML324AZ6102−3 HTHBIOTX015CEPGSK343RSC−01847325−−−33779015133 GandotinibRucaparibEnzastaurinOTX015CEPGSK343UNC0224RSC−−33779133 AZD5153Rucaparib Panobinostat EPZ004777ML324KW−2449 MIGSK126AZ6102HTHGandotinib−Cerdulatinib3ReversineOTX015UNC0224−01−015 AZDecernotinibRucaparibOTX015 960 PFI−4 OTX015CEP−33779 Trichostatin A UNC0638UNC0379SGC0946Etoposide AZD1480MIGSK126AZ6102−3 Kinase OTX015CEPAZD1480MIGSK126AZ6102−−333779 Other OTX015 DacinostatGandotinib 10 1 UNC0642LestaurtinibUNC0631TAK−901 10 1EtoposideAZKWZM 960 −4474392449 10 1 BMSTG101209AZD1480−911543 OF−1 AZD1480 AR−42 BIX01294EPZ005687PirarubicinUNC0631MILestaurtinibEnzastaurin−136 10 10 1 1MILestaurtinibMitomycin−WZ4003136Go6976Etoposide C 1010 11 FedratinibGo6976Etoposide 10 1 ApicidinHCHesperadin Toxin SGC0946UNC1999AuroraUNC0646 A Inhibitor I 10 Aurora 1BMSWZ4003CXJNJMILestaurtinib− −A9115436258136 −Inhibitor7706621 I 10 1 1 GSK1070916Go6976MILestaurtinib−136 10 (+) 1 −JQ1Go6976 concentrationNeplanocinMitomycin (µM)UNC0646MIAuroraDecernotinib−nc AC Inhibitor I concentrationMI Pirarubicin(µM)−HTHncAurora−01 A− Inhibitor015 I concentration (µM)WHIJNJ−−P1547706621 I−BRD9 TrichostatinCUDCAZ 960−101 A UNC0642EPZ004777SNSUNC0638−314 concentrationconcentration (µM)SNSGSK1070916 (µM)HTHGandotinib−NVPMI314−nc−−01BSK805−015 concentrationconcentrationconcentration (µM)(µM) (µM)MomelotinibAT9283JNJMIAurora−nc7706621 A Inhibitor I concentration (µM)JNJ−7706621 GSK503G007UNC0638UNC0379ASNS−−366LK−314 AG007−366SNS−LK−314 BisindolylmaleimideNVPNVPSNS−BSK805−314BSK805 IX concentrationRVX (µM)−208 ARAbexinostatCX−−426258 UNC1999GoBIX01294 6983 GoMomelotinib 6983AZTAKAGo− 960366 6983−901 DanusertibA−366 NVP−BSK805 LLYOF−−BIX01294EPZ005687SinefunginHesperadinGo507Pirarubicin1 6983 SinefunginCPIMitomycin−Sinefungin0610 C CYC116PacritinibTAKTAKGo− 6983901−901 PF−CBP1 HCPracinostatBI− Toxin847325 EPZ004777PinometostatSGC0946Hesperadin HesperadinBisindolylmaleimideBMSCerdulatinibHesperadin−911543 IX Sinefungin AZ6102TAK−901 CUDCGivinostat−101 PFI−NeplanocinUNC0224BIHesperadinMitomycin4−847325 AC UNC0224CPIPirarubicin−UNC0224637 SGITozasertibCerdulatinibCerdulatinibHesperadin−1776 Lestaurtinib HMT UNC0379MI−2UNC0642BI−847325 % inhibition BICYC116−847325GSK1070916KWBI−847325−2449 % %inhibition inhibition BarasertibKWUNC0224−2449 RSC−133Cerdulatinib AbexinostatBelinostat HMT% inhibition BromosporineGSK503GSK126ReversineBIG007−847325−LK % inhibition% inhibition% inhibition GSK126ReversineGSK6853SGIG007MomelotinibGSK126Reversine−1776−LK % %inhibition inhibition ENMDKWBI−847325−2449−2076 % inhibition SGI−1776 0 25EPZ005687A−50196UNC1999LLYReversine75−507100 0 0 2525 5050WZ40037575 100100 % inhibition 00 25 5050DecernotinibEnzastaurinWZ4003GSK126Reversine7575 100100 % inhibition RucaparibKW−2449 PracinostatCAY10603 CPIZMReversine−OF637 447439−1 0 250 2550ZMBromosporineBarasertib5075 CPI447439BisindolylmaleimideZM10075− 4474390610100 IX Kinase 00 25 5050 WZ40037575 100100 0 25 50 WZ400375 100 SNS−314 NeplanocinMI−463EPZ004777PinometostatLestaurtinibCXZM− 4474396258 A LestaurtinibCPIHTHLestaurtinibCX−−6376258−01−015 0 25 50TG101209CEPHTHHTHZM75− 4474393377901−01100−015−015 0 25OTX01550 75 100 GivinostatVorinostatGo 6983 B BRD4770I−BRD9UNC0379PFI−4 CXAZD5153Decernotinib−CPICYC1166258Aurora−637 A Inhibitor I FedratinibAZD1480Lestaurtinib HTH−01−015 CAY10398 HMT GSK503UNC0379MIAuroraGandotinibCXBromosporine−−26258 A Inhibitor I Kinase AuroraGandotinibEC50GSK6853Gandotinib A Inhibitor value I against CX−6258 10 1 BelinostatReversine HMT ChaetocinGSK6853EPZ005687ASNS−196−314 PFITG101209GSK6853SGI−MitomycinSNSAZ4 −9601776−314 C WHIGo6976MitomycinMitomycinAuroraGandotinib−P154 A CInhibitor C I CAY10603Coumarin−SAHA Other LLY−AZGandotinib507CPI 960−637 Other SNSAZ 960Bromosporine−Go314 6983 JNJPirarubicin−7706621 concentration (µM) Mitomycin C Aurora A Inhibitor I BabesiaPinometostatEI1RVXNeplanocinMIGoBMSBabesia−208− divergens6983463−911543 AA OtherHepG2Hep2G GoOFFedratinib 6983BromosporineBarasertib−PirarubicinBMS1Bd−911543(nM) ±SEM AT9283PirarubicinSNSAZ 960−314 HDAC VorinostatNexturastat A AZI−BRD9 960 BMS(+)AZD5153Decernotinib−−HesperadinGSK1070916JQ1911543 DanusertibNVPG007Go −6983−BSK805LK Pirarubicin MENMD 344 −2076 HMT MIGSK343CPI−2GSK503BRD4770HesperadinGSK1070916BMS−0610−911543 Kinase HesperadinGSK1070916(+)WHI−G007JQ1−P154−LK TAKCPIG007BMS−0610901−−911543LK CAY10398 DNMT MI−3ChaetocinBMSGSK6853−911543 PFITG101209BIMomelotinib−−8473254 PacritinibHesperadin G007−LK PyroxamideNVP−BSK805 Other RucaparibLLYBIMomelotinib−847325−−507507 Other SGI−1027BIMomelotinibIIAT9283−−BRD9847325PFICPIBisindolylmaleimide−−4061035.2 ± 0.2 IX CerdulatinibCPICPIGSK1070916−−6370610 Coumarin−SAHA DNMT AEtoposide−196EI1GSK1070916RVX−208 OtherOther OFFedratinibReversine−1 TozasertibBIMomelotinib−847325 CPI−0610 4BMS−iodo−−911543SAHA MIAZD5153−463PinometostatReversineBisindolylmaleimide IX ReversineBisindolylmaleimideRVXDanusertibOFCPIZMCYC116−−208 1447439−637 IX ENMDKWGSK6853CPI−1002449−−6372076 % inhibition Nexturastat A MI−136GSK343MomelotinibCPI−0610 (+)WHI−JQ1−P154 WZ4003ReversineBisindolylmaleimide IX 0 25 50 75 100CPI−637 HDAC LMKWZ4003−235 HMT BRD4770PF−MIZMCYC116CBP1− 24474392 Apicidin ZMCYC116PFPacritinib 447439(+)−GSK6853CXSGICBP1−−JQ1−625817766.1 ± 0.03 EnzastaurinBromosporineGSK6853 HDAC M 344 MI−ncMISGIBisindolylmaleimideARucaparib−−1963−1776 IX PFIAT9283−BarasertibCBP1BRD9 HTHAZD5153ZMCYC116− 44743901−015 GSK6853 NullscriptZM 447439 Chaetocin(+)−ACXJQ1−196−6258 AR−42 CXSGIAZ6102Tozasertib−−I6258−BromosporineGandotinib1776BRD9 CEPBromosporine−33779 PyroxamideScriptaid A−366EtoposideBarasertibCYC116MIAZD5153−463 AZ6102RVXDanusertibAZD5153AZDecernotinib 960−208160.4 ± 1.1 PFICXSGI−−4−62581776 Bromosporine GSK1070916 EI1OTX015MIGandotinib−463136 Kinase GandotinibBarasertibRSCENMDRVXTG101209−133−2076208 Other AZD1480MitomycinAZD5153 C 4Resminostat−iodo−SAHA SinefunginBRD4770DecernotinibSGIPF−−CBP11776 DacinostatDecernotinibRSCPFPacritinibPFIBMS−−133CBP1−−4111.9911543 ± 0.34 Go6976PirarubicinOFGandotinibBarasertib−1 AZD5153 AT9283 Kinase GSK343UNC0224RSCMIAZBarasertib−−133 960nc KinaseOther AZRucaparibEnzastaurin 960Fedratinib (+)PFIDecernotinib−75JQ1−4 LMKRicolinostat−235 HDAC ChaetocinBMSTG101209Barasertib(+)−−JQ1911543 TG101209RucaparibAZ6102TozasertibOFGSK1070916WHI−−1P154 KinaseOther JNJG007AZ− 9607706621−LK PFI−4 CYC116 MIGSK126AZ6102−3A−366 HC Toxin BMSOTX015CEP−−9115433377992.9 ± 0.45 CPII−OFTG101209BRD9−−06101 Other Kinase NullscriptThiomyristoyl HDAC EI1GSK1070916FedratinibDecernotinibOTX015 FedratinibOTX015RSCENMD(+)MomelotinibAT9283−−JQ1133−2076 NVPBMS−BSK805−911543 OF−1 ScriptaidMocetinostatBisindolylmaleimide IXKinaseKinase EtoposideSinefunginWHITG101209−P154 PanobinostatGSK1070916AZD1480Bisindolylmaleimide27.2 ± 0.05 IX CPIRVX(+)Fedratinib−−−637JQ1208 10 1 LestaurtinibGSK343UNC0224MomelotinibTG101209RSC−133 10 1 WHIRucaparibEnzastaurin−IDanusertib−P154BRD9 TAKIGSK1070916−BRD9−901 (+)−JQ1 ResminostatCBHAFedratinib MI−136AT9283Fedratinib 10 1 MomelotinibAT9283Go6976CEPCYC116Pacritinib−33779 CerdulatinibGSK6853PFWHI−50CBP1−P154 I−BRD9 AuroraMIGSK126BisindolylmaleimideFedratinibAZ6102 −A33 Inhibitor I IX QuisinostatBisindolylmaleimideOTX015RVXSGI−−17762084.6 ± 0.02 IX BromosporineAZ6102RVXMomelotinibAT9283−208 RicolinostatTenovinTG101209−6 concentration (µM)MI−ncDanusertibWHIEtoposide−P154 concentration (µM)DanusertibJNJAZD1480Tozasertib−7706621 KWBisindolylmaleimide−2449 IX RVX−208 Oxamflatin SNSEtoposideCYC116Pacritinib−WHI314−P154 Trichostatin10 1CYC116 NVPA PFBarasertibENMD−BSK805−CBP1278.2−2076 ± 0.86 WZ4003AZD5153RSCPFDanusertib−−CBP1133 ThiomyristoylPacritinib 10 A1−366MILestaurtinibAT9283−136136 10 1PacritinibGo6976 PFIRucaparibCYC116−4 PF−CBP1 Citarinostat Go 6983AuroraSGITozasertib−1776 A Inhibitor I Kinase SGITozasertibTAK−AZ6102DecernotinibEnzastaurin1776−901 Other HTHAZ6102Pacritinib−01−015 MocetinostatMomelotinib concentrationSinefunginHesperadin (µM)MIDanusertib−ncnc concentration (µM)JNJRSCTG101209CEP−7706621−−33779133 OFOTX015SGITozasertib−1−1776 AZ6102 CBHATubastatin A UNC0224SNSBarasertibENMD−314−2076 BIX01294BarasertibENMDCerdulatinib−2076252.0 ± 0.82 (+)RSC−25JQ1−133 SRT1720HTH−01−015 BI−847325ADecernotinibEnzastaurinPacritinib−366366 NVPRucaparibFedratinibAZD1480−BSK805 10 1 MitomycinBarasertibENMD−2076 C RSC−133 Tenovin−6 % inhibitionKinase GSK126Go 6983 % inhibition SGC0946DecernotinibEnzastaurinKWTAK−WHIGo69762449−−901P154 I−RucaparibBRD9 Barasertib ReversineSinefunginTozasertib Kinase% inhibition 136.8 ± 0.93 inhibition % PirarubicinDecernotinibEnzastaurin Rucaparib SRT2104 HesperadinTG101209CEPTozasertib−33779 0 25 50TG101209CEPWZ400375−OTX015JNJ33779100−7706621 Kinaseconcentration (µM)RVXOTX015−208 OxamflatinWHI−P154 0 25 50ZM75 447439UNC0224AZD1480ENMD100 −2076 UNC06310 25 50 75CerdulatinibAT9283100 G007PFTG101209CEP−CBP1−−LK33779 OTX015 CitarinostatJIB−04 LestaurtinibBIFedratinibENMD−847325−2076 10 1FedratinibAZD1480HTHDanusertibNVP−01−−BSK80543.4015 ± 0.14 CPI−0610 Tozasertib %HMT inhibition CX−6258GSK126ReversineGo6976Enzastaurin % inhibition KWTAK−−2449901 10 1 AZ6102FedratinibAZD1480 TubastatinSP2509 A HMT AuroraWHIEnzastaurin A −InhibitorP154 I UNC06380 25 WHIGo697650 −Pacritinib75P154100375.5 ± 1.39 CPI−637 10 1 HDM AZD1480 0 25Gandotinib50ZMAT9283JNJCEP75 447439−−770662133779100 concentration0 25 JNJ50 (µM)−WZ4003Cerdulatinib770662175 100 concentration (µM)RSCWHIGo69760−−133P154 SRT1720GSK−J4 SNSLestaurtinib−CEP314−33779 AT9283MitomycinHTHTozasertib−01 −C015 GSK6853RucaparibJNJ−7706621 concentration (µM) CEP−33779 AZ 960CXDanusertibNVPAZD1480−6258−BSK805 UNC0642NVP−ENMDKWBSK805−2449466.6−2076 ± 1.51 % inhibition AT9283 SRT2104ML324 Go 6983AuroraAZD1480 AA InhibitorInhibitor II DanusertibPirarubicinWZ4003 0 25 50 BromosporineOTX015NVP75 100−BSK805 Go6976 BMSGandotinibPacritinibTAKGo6976−911543−901 UNC0646TAK−Enzastaurin901 AZD5153Danusertib HesperadinGSK1070916SNSAZCerdulatinibGo6976 960−−314314 PacritinibG007MitomycinHTH−LK−199.901−015 C ± 0.75 10 1 TAK−901 JIBUNC0631Danusertib−04 TozasertibJNJ−7706621 TozasertibCerdulatinibPirarubicinCEP−33779 PFIPacritinib−4 UNC0646 BIMomelotinib−847325GoBMSKW 6983−−2449911543 % inhibition KWCPI−2449AZD1480Mitomycin−0610 C % inhibitionOtherconcentration (µM)TozasertibCerdulatinib SP2509JNJ−7706621 HesperadinENMDNVP−BSK805−2076 Aurora A InhibitorENMDCPIG007−637− I2076−134.5LK ± 0.51 OFKW−1−2449 % inhibition HDM UNC0638Cerdulatinib Kinase ReversineBisindolylmaleimideGSK1070916WZ4003TAKHesperadin−901 IX 0 25WZ400350 Go6976Pirarubicin75 100 0 25 50(+)ENMD75−JQ1100−2076 GSK−J4 Kinase CYC116BIMomelotinibEnzastaurinHTHTAK−847325847325−−90101−015 LestaurtinibEnzastaurinGSK6853CPIJNJG007−−06107706621−LK WZ4003 0 25 50 75 100 BIX01294KW−2449 ZM 447439CEPCerdulatinib−33779 HTH−01−01587.9 ± 0.27 I−EnzastaurinBRD9 ML324SGC0946 CXSGI−−6258ReversineBisindolylmaleimideCerdulatinib1776 IX CEPBromosporineCPI−NVPCPI33779−−637−0610BSK805 RVXHTH−208−01−015 TAK−901 AZD1480MitomycinKW−2449 C CPI−637 % inhibition CEP−33779 UNC0642 Other GandotinibBarasertibZMCYC116KW 447439−4474392449 Mitomycin AZD1480MitomycinCAZD5153GSK6853TAK−901 C64.0 ± 0.24 0 25 50 PF75−CBP1100 UNC0631Enzastaurin Other SGIGo6976PirarubicinWZ4003−1776 Go6976PirarubicinBromosporineCerdulatinibGSK6853 AZD1480Mitomycin C UNC1999 Kinase AZDecernotinib 960CXWZ4003−−62586258 PFI−Bromosporine4 AZ6102Go6976Pirarubicin UNC0646EPZ004777Decernotinib 1000 360 TG101209120 BarasertibJNJG007HTH40−−7706621−01LK−13015 4 1 Other1000 JNJG007−AZD5153KW7706621−LK−2449 RSC−133 UNC0638 1000 360 BMS120GandotinibCPIHTH−91154340−−06100113−015 4 1 1000 OF−AZD51531 JNJG007−7706621−LK UNC0379 Kinase FedratinibAZDecernotinibNVP 960−BSK805 NVPCPI−PFI−WZ4003PFI0610BSK805−−44 Rucaparib BIX01294Pirarubicin GSK1070916concentrationTG101209CPIMitomycin−637 C (nM) OtherOther CPI(+)−−HTH637JQ1−01−015 NVPCPI−−0610BSK805 EPZ005687 WHI−BMSTAKMitomycinP154−−−901911543911543 C TAKOF−OF901−−11 OTX015CPI−637 SGC0946NeplanocinMitomycin AC concentrationMomelotinibFedratinibCerdulatinibGSK6853Pirarubicin (nM) GSK6853I−BRD9(+)−JQ1 TAK−901 AT9283GSK1070916BromosporinePirarubicin Cerdulatinib(+)Mitomycin−JQ1 C 10 1 GSK6853 UNC0642GSK503G007−LK BisindolylmaleimideDanusertibWHIKWG007−−2449−P154LK IX BromosporineRVXI−I−BRD9−BRD9208 Cerdulatinib UNC1999 CYC116MomelotinibAT9283AZD5153G007−LK KWAZD5153PF−−2449PirarubicinRVXCBP1−208 concentration (µM)Bromosporine LLYOF−−5071 PacritinibBisindolylmaleimideWZ4003CPI−0610 IX WZ4003RVXG007−208−LK KWAZD5153−2449 EPZ004777Pinometostat % inhibitionSGI−DanusertibPFICPIBisindolylmaleimide1776−−40610 IX PFIAZ6102−4PF−CBP1 WZ4003 PFI−4 Figure 2. OtherActivity of epigeneticTozasertibCYC116HTHCPI−−63701−015inhibitorsOtheragainst BabesiaHTHPF−CPIAZ610201−CBP1−divergens0610015 . (A) 125 compoundsPFI−4with ≥50% HMT UNC0379MI−2 BarasertibPacritinibOFCPICYC116−−1063725 50 75 OFRSC−1 −133 Other HTH−01−015 HMT Bromosporine ENMDSGITozasertib(+)GSK6853−−2076−−JQ117761776 AZ6102CPIRSC−−637133 OF−1 EPZ005687A−196 inhibition at 10 µM. HeatmapDecernotinibEnzastaurinMitomycinof mean C percent inhibition at (+)10Rucaparib−JQ1andGSK6853Rucaparib1 µM compared to solvent-treated controls CPI−637 Kinase BarasertibENMDIBromosporine−BRD9−2076 MitomycinI−BRD9RSC−133 C % inhibition Mitomycin(+)−JQ1 C NeplanocinMI−463 A TG101209CEPPirarubicin−33779 PirarubicinOTX015RucaparibBromosporineOTX015 0 25 50 I75−BRD9100 BRD4770I−BRD9 (n=3). Compounds are groupedDecernotinibEnzastaurinRVXAZD5153−208 based on the reported epigeneticRVX−AZD5153208 process affected in higherPirarubicineukaryotes: GSK503 Kinase FedratinibAZD1480TG101209CEPG007PFPFI−−CBP1−4−33779LK 10 G0071 OTX015−LK RVX−208 LLYChaetocinGSK6853−507 Other Go6976PFITG101209−4 10 1 PF−CBP1PFI−4 G007−LK Other Other WHI−FedratinibAZD1480CPIAZ6102OFP154−−10610 OtherconcentrationCPIAZ6102 (µM)−0610 PF−CBP1 PinometostatEI1RVX−208 Histone Otherdeacetylation (HDAC),JNJ−CPIOFFedratinib7706621−−1637histone acetylationconcentration(HAT),10 (µM)1histoneOF−1 methylation (HMT), HistoneCPIAZ6102Demethylases−0610 GSK343CPI−0610 AT9283WHIGo6976RSC(+)−JQ1−−P154P154133 CPIRSC−−(+)637133−JQ1 HMT MI−2 DanusertibNVPJNJGSK6853Rucaparib−(+)BSK805−−JQ17706621 concentration (µM) CPIRSC−−637133 MIRucaparib−3 (HDM), DNA methylation AT9283I(DNMT),−BRD9 and “Other”. (B) DoseGSK6853RucaparibresponseI−BRD9 analysis for 17 compoundsGSK6853with sub- A−196 PacritinibTAK−NVPBromosporineOTX015I−901BRD9−BSK805 BromosporineOTX015RVX−208 Rucaparib EtoposideAZD5153 CerdulatinibDanusertibRVX−208 % inhibition BromosporineOTX015 MI−463136 micromolar EC50 valuesTozasertib(n=PacritinibTAKAZD5153RVX2−),−901208with corresponding HepG0 225AZD5153inhibition50 PF75−CBP1100 at 1 µM. BRD4770PF−CBP1 10 1KW−CerdulatinibPFPacritinib2449−CBP1 % inhibition10 1 AZD5153 MI−nc Other ENMDTozasertibPFI−2076−4 PFI−4AZ6102 10 1 ChaetocinA(+)−366−JQ1 concentrationWZ4003 (µM)KWOFAZ6102Tozasertib−−12449 Other%concentration inhibition0 25 (µM)50 75RSC100−133 PFI−4 EnzastaurinHTHENMD−RSC01−−015133−−20762076 OF−1 Otherconcentration (µM) EI1SinefunginOTX015 WZ4003(+)RSC−JQ1−133 0 25 (+)50−JQ1Rucaparib75 100 OF−1 CEPEnzastaurinHTH−Rucaparib33779−01−015 OTX015 (+)−JQ1 GSK343UNC0224RSC−133 AZD1480MitomycinCEPIRucaparib−BRD9− 33779C I−BRD9 MIGSK126AZ6102−3 RVXOTX015CEP−−20833779 10 1 I−BRD9 % inhibition Go6976PirarubicinAZD1480Mitomycin C % inhibition RVX−208 Etoposide 0 25 50 PF75−CBP1100 % inhibition RVX−208 10 1 Lestaurtinib 10 1JNJG007−Go6976Pirarubicin7706621−LK concentration0 25 50 PF75 (µM)−CBP1100 MI−136 CPI−JNJG007AZ61020610−7706621−LK 0 25 50 PF75−CBP1100 Aurora A Inhibitor I concentrationNVP (µM)−JNJBSK805−7706621 AZ6102 AZ6102 concentration (µM)MISNS−nc−314 concentrationCPI (µM)−NVPCPIRSC637−−0610BSK805133 RSC−133 A−366 TAK−CPINVP901−−637BSK805 RSC−133 Go 6983 CerdulatinibGSK6853TAKRucaparib−901 Rucaparib Sinefungin BromosporineGSK6853OTX015TAK−901 % inhibition Rucaparib Hesperadin KW−Cerdulatinib2449 0 25OTX01550 75 100 UNC0224BI−847325 AZD5153KWBromosporine−2449 OTX015 % inhibition GSK126Reversine % inhibition10 1WZ4003PFI−AZD5153KW4 −2449 10 1 Other 0 25HTH50 WZ4003PFI−0175−−4100015 10 1 0 25 50ZM75 447439100 Otherconcentration0 25OF (µM)50−1HTH75 −10001−015 concentration (µM) LestaurtinibCX−6258 (+)−JQ1OFHTH−1−01−015 concentration (µM) AuroraGandotinib A Inhibitor I Mitomycin(+)−JQ1 C I−BRD9MitomycinI−BRD9 CC SNSAZ 960−314 PirarubicinRVX−Pirarubicin208 GoBMS 6983−911543 % inhibition G007RVXPirarubicin−LK−208 PF−CBP1G007PF−CBP1−−LKLK % inhibition HesperadinGSK1070916 0 25 CPIAZ610250−CPI061075−0610100 0 25 50 75 100 % inhibition BIMomelotinib−847325 CPI−AZ6102CPI637−0610 0 25 50 75 100 RSCCPIRSC−133−−637133 ReversineBisindolylmaleimide IX GSK6853RucaparibGSK6853CPI−637 CYC116 RucaparibGSK6853 ZM 447439 BromosporineOTX015BromosporineOTX015 CXSGI−−62581776 AZD5153Bromosporine Barasertib 10 10 1 1 AZD5153 Gandotinib PFI−PFIAZD51534 −4 AZDecernotinib 960 OtherconcentrationOtherconcentration (µM) (µM)PFI−4 Kinase TG101209 Other OF−1OF−1 BMS−911543 (+)−JQ1(+)OF−−JQ11 Fedratinib (+)−JQ1 GSK1070916WHI−P154 I−BRD9I−BRD9 Momelotinib RVX−RVXI−208BRD9−208 AT9283 % inhibition% inhibition RVX−208 BisindolylmaleimideDanusertib IX 0 250 5025PF7550−CBP1PF10075−CBP1100 CYC116Pacritinib AZ6102AZ6102PF−CBP1 SGITozasertib−1776 RSCRSC−AZ6102133−133 BarasertibENMD−2076 RucaparibRucaparibRSC−133 DecernotinibEnzastaurin OTX015Rucaparib Kinase TG101209CEP−33779 OTX015OTX015 10 1 FedratinibAZD1480 10 10 1 1 WHIGo6976−P154 concentrationconcentration (µM) (µM) AT9283JNJ−7706621 concentration (µM) DanusertibNVP−BSK805 PacritinibTAK−901 TozasertibCerdulatinib % inhibition KW−2449 % inhibition% inhibition 0 25 50 75 100 ENMDWZ4003−2076 0 250 5025 7550 10075 100 EnzastaurinHTH−01−015 CEP−33779 AZD1480Mitomycin C Go6976Pirarubicin JNJG007−7706621−LK NVPCPI−−0610BSK805 TAKCPI−−637901 CerdulatinibGSK6853 Bromosporine KWAZD5153−2449 WZ4003PFI−4 Other HTHOF−1−01−015 (+)−JQ1 MitomycinI−BRD9 C PirarubicinRVX−208 G007PF−CBP1−LK CPIAZ6102−0610 CPIRSC−−637133 GSK6853Rucaparib BromosporineOTX015 10 1 AZD5153 PFI−4 Otherconcentration (µM)OF−1 (+)−JQ1 I−BRD9 % inhibition RVX−208 0 25 50 PF75−CBP1100 AZ6102 RSC−133 Rucaparib OTX015 10 1 concentration (µM)

% inhibition 0 25 50 75 100 SGI−1027 Quisinostat 100100 ● A Panobinostat UNC0631 Lestaurtinib Mitomycin C ● Dacinostat 100100 ● ● ● ● 9595 UNC0646 Apicidin

SGC0946 SNS−314 (%) µM 1 at Trichostatin A UNC1999 ● AR−42 Reversine ●● ● ● Aurora A Inhibitor I UNC0638 ● Go 6983 ● ● targetCategory ●a DNMT 100 EPZ004777 ● 9090 BI−847325 UNC0642 100 ● ● a HAT 100100 100 ● ● HC Toxin BIX01294 100 ● inhibition ● ● ● ● a HDAC ● ● ●● CUDC−101 SGC09467575 SNS−314 ● ● ● ●● ● Abexinostat a HDM SGC0946UNC1999 SNS−314 ● SGC0946 SGC0946UNC1999SNS−314 SNSSNS−314−314 ● ● a HMT Reversine SGC0946 UNC1999SGC0946Gandotinib UNC1999SNS●● −314 ● ● ● ● 8585 Reversine● Reversine UNC1999 UNC1999Go 6983 ● ●● ● ● ● ● ●a Kinase Reversine● ReversineReversine● ● ● Go 6983 ●●●● ● ● ●● ● ● Pracinostat 100 100 ● ● Go 6983●● GoGo 6983 6983 ● ● ● ● Belinostat ●a Other ● (%) Babesia inhibition at 1 µM Givinostat EPZ004777● Go 6983 ● ● targetCategory● ● EPZ004777EPZ004777 100 divergensB. 100 100 (%) µM 1 EPZ004777 at EPZ004777 ● ● ● ● ●a●DNMT ● EPZ004777 EPZ005687 ● SGC0946 SGC0946 SNS−314 SNS−314 ● ●● ●● ● ●● a HAT●8080 ZM 447439 UNC1999 ● ● 75 UNC1999 ● ● a HDAC● Reversine SGC0946ReversineSGC09465050 SGC0946 SNS−SNS314−314 ●SNS−●314 ● UNC0379 75 75 ●●UNC1999 ● ● ● ● ● ● a HDM ● ● 75 75 ● UNC1999GoUNC1999 6983 Go 6983 ● ● ●● ReversineReversineReversine ● ●● ●● ● ● ● ● ● ● CAY10603 75 inhibition ● ● ● ● ● a HMT ● ●Gandotinib Go 6983Go 6983 Go 6983 ● ● ● ● ●● EPZ004777 GandotinibEPZ004777 ● ● ●a Kinase7575 ● ● GandotinibGandotinibGandotinib GSK1070916 ● EPZ004777EPZ004777●EPZ004777 ● ●a Other ● ● 75 80 85 90 95 100 Gandotinib (%) Babesia inhibition at 1 µM ● ● 75 80 85 90 100 ● ● targetCategoryPlasmodium inhibition at 1 µM (%) ● ● ● targetCategory ● ●● P. falciparumtargetCategorytargetCategorytargetCategory inhibition at 1 µM (%) 75 ●● ● ●a DNMT 75 EPZ00568775 ● ● SGI−1776 ●a DNMT 75 75 EPZ005687 ● ● targetCategory●a●a DNMTDNMT B. divergensB. 25 EPZ005687 ● 25 EPZ005687EPZ005687● ● Barasertib ● aa HATHAT ● ● TG101209 ● ● HAT Gandotinib ● ● ● Resminostat ● LLY−507 ● ●a DNMT aa HAT Gandotinib EPZ005687 Gandotinib● ● ●● aa HDACHDAC 50 GandotinibGandotinib● 50 ● ● ● Ricolinostat Fedratinib Targeta HAT categoriesaa HDACHDAC 50●50 ● ● ● aa HDMHDM 50 ● ● ● ● Chaetocin 3−Deazaneplanocin A MI−463 HDAC targetCategorytargetCategoryaa HDMHDM targetCategorytargetCategoryaa HMTHMT 50 ● ● ● ENMD−2076 MI−136 shortName ● ●●● ● ● ● ●a●a DNMTHMTHMTDNMT ● EPZ005687EPZ005687● ● ● ● ● ●a●a HDMKinaseKinase ●●●●●●● ●● ● AZD1480 GSK1070916GSK1070916 ●a●a DNMTDNMT EPZ005687EPZ005687EPZ005687●●●●● ●● ●● ● ●a●a HATKinaseKinaseHATKinase ● ●●● ●●●●●●●● ●● ● ● CUDC−907 Amodiaquine SRT1720●● GSK1070916●a●a HMTOtherOther a 0 ●●●●● ●●●●●● ●●● ●● ● ● ● ● GSK1070916aa HATHAT Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM 0 ● ● ● ●●● ●● ●a●a HDACOtherOtherHDAC 50● Kinase a Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM

Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM a Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM SAHA ●aa HDACHDAC 50 ●● GSK1070916− a HDAC HDM 50 50 ● 0 25 10150 75 SAHA 100 907 a HDM 2076 50 ● 0 ● ● 25 − 50 75 − 235 100 − Other a shortName 314 − 1027shortName ● ●●●Plasmodium inhibition at 1 µM (%) − ● ●aa HDMHDM 04 507 − 1776 − ● 42 a HDM a HMT − 463 136 847325 6258 − Babesia inhibition at 1 µM (%) Babesia inhibition at 1 µM ● ● −● iodo SGISGI−−17761776 − shortName − − − ●●●●● P. falciparum inhibition at 1 µM (%) − a HMT Deazaneplanocin A − GemcitabineSGI QuisinostatPanobinostatDacinostatApicidinshortNameTrichostatinAR ABelinostatNexturastatHC Toxin AAbexinostatCUDCPracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 3444 LMK CoumarinRicolinostatResminostatTubastatinCUDC A SRT1720a HMTHMTJIB EPZ004777shortNameSGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC0379− ChaetocinLLY MI MI ReversineGandotinibGo 6983SNS Hesperadin LestaurtinibAZ 960BI ZM 447439CX AZD1480BarasertibENMDGSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C 25 ● ● ●● SGISGI−−17761776aa HMT ●a Kinase 3 Aurora A Inhibitor I ● ● ● BarasertibBarasertib TG101209 GSK1070916 a Kinase conc_nM

● 2525 25● ● TG101209 ●● KinaseKinase ●

● ● ●●● ● ● SAHA GSK1070916●a●a ●a Other ● Barasertib delta ● ● ● ResminostatResminostat ● BarasertibBarasertibGSK1070916GSK1070916−TG101209TG101209LLYLLY−−507507 ● ●a Kinase SAHA (%) Babesia inhibition at 1 µM TG101209 ● ● ● 101 SAHA●● SAHA 907 ●a Other 2076 − SAHA ● ● ● ● ● − ●− GSK1070916●● SGI− SAHA−1776 ●− a OtherOther shortName − SAHA − ● ● 1027 Resminostat ●● 235 −● 2076 LLY●a●−507 shortName 507 314 1776 1 µM 101 907 (%) Babesia inhibition at 1 µM Ricolinostat Resminostat Fedratinib − ● ●shortName− 42 101 Resminostat SAHASAHA− LLY907LLY−−50750704 shortName 463 136 − 6258 20762076 − − (%) Babesia inhibition at 1 µM SAHA − 101 Fedratinib − 907 − 101 235 (%) Babesia inhibition at 1 µM ● 907 ● − Ricolinostat − 314 − ● 2076− ●a − Other 847325 − − 1027 − − − 23525 ●04 − ● ● 1027 ● 507 − − 314 iodo − 235235 ● ●●●● − − 1776 Deazaneplanocin507 A − − 314314 − − 1776 − 42 1027 42 − 04 −1027 42− 463 136 507 − − −−6258 6258 ● −04041776 − 507 463 136 − − 62586258 − 1776 − − (%) Babesia inhibition at 1 µM − B ●●● − ●Apicidin AR − HC− Toxin 463 136 M 344847325 − FedratinibSRT1720 JIB− − LLY−− MI 463MI 136 Go 6983 AZ 960 847325847325 CX− AZD1480 − − iodo ●− GemcitabineSGI QuisinostatPanobinostatDacinostat DeazaneplanocinTrichostatin− A Belinostat A●− Nexturastat− A AbexinostatRicolinostatCUDCRicolinostatPracinostatGivinostatPyroxamideCAY10603BarasertibVorinostatCAY10398 4 iodo847325LMK Coumarin− RicolinostatResminostatTubastatinFedratinibCUDC A − EPZ004777SGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC03793DeazaneplanocinChaetocin A −− −− ReversineGandotinib SNS HesperadinAurora ALestaurtinib Inhibitor I BI ZM 447439− BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C − iodo ● ●● ● ● ● ● ●Deazaneplanocin A − Ricolinostat− Chaetocin − −TG101209iodo− Fedratinib Deazaneplanocin A − − − ● ● ● GemcitabineSGI Quisinostat●Panobinostat● ●DacinostatApicidinApicidin− AR Belinostat− HC ToxinAbexinostatCUDC PracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 344344 − LMKLMK RicolinostatResminostatTubastatinCUDC A SRT1720SRT1720JIBJIB EPZ004777SGC0946SGC0946UNC1999UNC1999EPZ005687UNC0631UNC0631UNC0646UNC0646UNC0638UNC0638BIX01294BIX01294UNC0642UNC0642UNC0379UNC0379−− ChaetocinLLYLLY MIMI MIMI ReversineReversineGandotinibGoGo 6983 6983SNSSNS Hesperadin LestaurtinibAZAZ 960 960BI ZM 447439CXCX AZD1480AZD1480BarasertibENMD TG101209FedratinibFedratinibSGI PirarubicinMitomycinAmodiaquine C

GemcitabineSGI QuisinostatPanobinostatDacinostatApicidinTrichostatinGemcitabineAR SGI A BelinostatQuisinostatNexturastatPanobinostatHC Toxin DacinostatA AbexinostatApicidinCUDCTrichostatinPracinostatAR AGivinostatBelinostatPyroxamideNexturastatHCCAY10603 Toxin AAbexinostatVorinostatCUDCCAY10398PracinostatM 344Givinostat4 PyroxamideLMKCAY10603CoumarinVorinostatRicolinostatCAY10398ResminostatM 3444TubastatinLMKCUDC ACoumarinSRT1720RicolinostatJIBResminostatDNMTTubastatinEPZ004777CUDC ASGC0946●SRT1720●UNC1999JIBEPZ005687EPZ004777UNC0631GemcitabineSGC0946UNC0646SGIUNC1999UNC0638EPZ005687QuisinostatBIX01294UNC0631PanobinostatUNC0642UNC0646DacinostatUNC0379UNC06383BIX01294TrichostatinTrichostatinUNC0642ChaetocinUNC0379LLY 3AA●3−MIDeazaneplanocinChaetocinNexturastatMI LLY AAReversineMIAbexinostatHDACMIGandotinibCUDCGo PracinostatReversineA 6983ChaetocinSNSGandotinibGoHesperadinPyroxamide 6983SNSAuroraCAY10603Hesperadin ALestaurtinib InhibitorAuroraCAY10398AZ I960 LestaurtinibA InhibitorBI AZ 49604 ZMI BI 447439CXZM 447439CoumarinCoumarinAZD1480CX RicolinostatBarasertibAZD1480MIResminostat−BarasertibENMD463TubastatinENMDGSK1070916GSK1070916CUDCTG101209 ATG101209FedratinibFedratinibSGISGIHDMPirarubicinEPZ004777PirarubicinMitomycinMitomycinAmodiaquine C EPZ005687 3HMT3 Chaetocin Gandotinib HesperadinAuroraAurora A LestaurtinibAInhibitor Inhibitor I I BI ZM 447439 BarasertibENMDGSK1070916GSK1070916TG101209Kinase SGI PirarubicinMitomycinAmodiaquine C Other

● conc_nM

● ● ● ● ● ● 3●−Deazaneplanocin● ● AResminostat LLY−507 SGI−1776 conc_nM

● ●● ●●●●● ● ● ● Chaetocin MISAHA−463 babesia

SAHA ● ● ● ● ● ● ChaetocinChaetocin ● −SAHA shortName

− babesia ENMD−2076 conc_nM delta ● − 25 3−Deazaneplanocin101 A SAHA● − 907● delta 2076 MI−463 babesia 101 SAHA ● ●907 ● ● ● 3−3Deazaneplanocin−Deazaneplanocin−101 ENMD−2076 A A −SAHA235MI−136SGISGI−1776 2076SGIMI−−907−1776463 -100 -50 0 50 100 314 −2076 1 µM 101 Barasertib 907 conc_nM − − ● ●● ●− ● 1027 42 Ricolinostat − − −235MIFedratinib−136TG101209− MI−− 463 04 507 −314 6258 − 1776 235 ● ● ● 314 1 µM conc_nM 1 µM 1027 − ● ●Delta04 −1027 −42 507 ● − −235 −041776 −507 463 136 −314 847325 −6258 −1776 1 µM − 42 ●●25●● ● ● − ● 42 ● − 463 136 iodo − 6258 ● 04− 1 µM Deazaneplanocin− A −463 −136 − 847325 6258 − − 25 25 ●●●●● ●●● ● ●●− ● −● ● − AZD1480− ●− ● ENMDENMD−−20762076−iodo●847325 −SGI−●1776 − − − − −847325 − − iodo ● ● ●● ● ●● SGI Quisinostat DacinostatApicidin ●AR ●BelinostatDeazaneplanocinHC Toxin A CUDC PracinostatGivinostat CAY10603ResminostatENMDVorinostatCAY10398−2076M 344 −iodo− LMK Ricolinostat MI−CUDC136SRT1720LLY−JIB507 SGC0946UNC1999 UNC0631UNC0646UNC0638BIX01294UNC0642UNC0379−DeazaneplanocinChaetocinLLY AMI− MI− ReversineGandotinibGo 6983SNS Hesperadin AZ 960BI− ZM 447439CX AZD1480Barasertib TG101209FedratinibSGI Pirarubicin − ●●●●● ● ●● Gemcitabine● SGI Panobinostat●ApicidinTrichostatinAR A Belinostat− NexturastatHC Toxin AAZD1480Abexinostat GivinostatPyroxamideBarasertibBarasertibVorinostat MBarasertib 344 4− LMK Coumarin ResminostatMITubastatinMI−136−136 A SRT1720 JIB EPZ004777SGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC03793− ChaetocinLLY MI MI Reversine Go 6983SNS Aurora ALestaurtinib InhibitorAZ I960 CX AZD1480BarasertibENMD GSK1070916 FedratinibSGI MitomycinAmodiaquine C GemcitabineSGI QuisinostatPanobinostatDacinostatApicidinTrichostatinAR A BelinostatNexturastatHC Toxin A AbexinostatCUDC PracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 344 4 LMK CoumarinRicolinostatResminostat●●Tubastatin● ●CUDC A●SRT1720●●● JIB●●●●●●EPZ004777●●GemcitabineSGC0946● SGIUNC1999● EPZ005687QuisinostatUNC0631PanobinostatUNC0646DacinostatUNC0638ApicidinBIX01294TrichostatinUNC0642●●ARUNC0379 A Belinostat3 ● ChaetocinNexturastatLLYHC Toxin AMIAbexinostatMICUDC PracinostatReversineGandotinibGivinostatGoPyroxamide● 6983SNSCAY10603HesperadinVorinostatAurora●CAY10398 ALestaurtinib InhibitorM 344AZ I9604TG101209TG101209BI LMKZM 447439CoumarinCX RicolinostatTG101209AZD1480ResminostatBarasertib●TubastatinENMD GSK1070916CUDC A TG101209SRT1720FedratinibJIBSGI EPZ004777PirarubicinSGC0946Mitomycin% inhibitionUNC1999Amodiaquine C EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC03793 ChaetocinLLY MI MI ReversineGandotinibGo 6983SNS HesperadinAurora ALestaurtinib InhibitorAZ I960BI ZM 447439CX AZD1480BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C

25 ●●●●●●● ●●●●●●●●●●●●● ● ● ● Chaetocin●CUDC● −907●● Amodiaquine●SRT1720● −75−50−250 255075100

DNMT HDAC ●● ●● ●●●●●HDM●●●●●●●●●DNMT ●● HMT ● ● ●RicolinostatHDACAZD1480AZD1480 ●● ●Kinase SAHA FedratinibHDM Other % Delta (Pf – BdHMT) inhibition Kinase Other

● ●●● ●●●●●●●●●●●● ● 3−Deazaneplanocin● Resminostat A AZD1480CUDCBarasertibResminostat−907 Amodiaquine− SRT1720 LLY−507 babesia

● ● ● ●●●●●● ● Resminostat LLY−507 plasmodium babesia ● ●● ● MI−463 babesia 0 ●● ● ●●●●●●●● ● ● ● TG101209 babesia ●●●●●●●●●●●●●●●●●●● ●●● ● ● ● ● ● 101 SAHA ● 907 2076 plasmodium

● ●●● ●●●●●●● ● ●●●● ● − ●● ● − conc_nM

− − conc_nM conc_nM ● ● ● ● ● conc_nM

0 ●●●●●● ●●●●●●●●●●●●●● ●●●● 1027●●● ● ● ● ● ● CUDC−907 ●235● Amodiaquine●● SRT1720 314 1776 1 µM ● ●● ●●●●●● ●●●●●●● 42 ● ● CUDC−907 − Amodiaquine SRT172004 plasmodium 1 µM 507 − 6258 11 µMµM ● ●●●●●●●●● ●●●●●●−●●● − Ricolinostat ResminostatRicolinostatENMD−2076ChaetocinCUDC−907 FedratinibFedratinibAmodiaquineLLY−Fedratinib507 SRT1720− − 463 136 847325 − − 1 µM 0 ●●Bd●●●●●●●●●●●●●●●●●●●●● ●● ● ● ● Ricolinostat iodo MI−136 ● Deazaneplanocin A − − − ●● ● 0 ●● ●●●●●●%●● inhibition●●●●●●● ●●● ●● ● ● ● 3−Deazaneplanocin A − ● ● % inhibition − ●● 0●●●●●●●●●●●●●●●Gemcitabine●● SGI●●● Quisinostat●●Panobinostat●DacinostatApicidin●Trichostatin●AR ● A BelinostatNexturastatHC Toxin A Abexinostat●CUDC PracinostatGivinostat●PyroxamideCAY10603VorinostatCAY10398M 344 4 LMK● CoumarinRicolinostatResminostatTubastatinCUDC AMISRT1720●−463JIB EPZ004777SGC0946UNC1999EPZ005687UNC06310 UNC0646251UNC0638 µM50BIX0129475UNC0642100UNC03793 ChaetocinLLY MI MI ReversineGandotinibGo 6983SNS HesperadinAurora ALestaurtinib InhibitorAZ I960BI ZM 447439CX AZD1480BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C

0● ●● ●● ●●● ● −75−2550−250 255075100 ● Ricolinostat●●●● 50 ●AZD1480 75 Fedratinib 100 −75−50−250 255075100

● ● ●●●●● ●● ●● DNMTDNMT ● ● ChaetocinHDACChaetocinChaetocinENMD−2076 HDMHDM HMTHMT KinaseKinase OtherOther

● plasmodium babesia ● plasmodium

0● ● ● 25 50 75 100MI−136 plasmodium ●● ●● ●● Plasmodium3●−Deazaneplanocin3 −inhibitionDeazaneplanocin3− Deazaneplanocinat 1 µM A (%)A A MIMI−463 MI−463 plasmodium ● ●● ●● 0●● ● ●● ● ● 25 ● 50 CUDC● −907● Amodiaquine75 SRT1720 100 1 µM conc_nM DNMT HDAC ● ●HDM● ●● ●●●●●●●0●●●●● HMT● Plasmodium25 inhibition at ●1 µMChaetocin (%)50 AZD1480 Kinase 75 100 Other 1 µM 11 µMµM 0 ●●●●●●●●●●●Pf0●●● ●●● ●●●●●● ● ●25●3−Deazaneplanocin● A 50 ENMDENMD−2076−2076ENMD−2076 75 MIMI−−136136● 100 % inhibition ● ●● ●● ●●● ● ● ●● Plasmodium● inhibition at 1 µM (%) CUDC−907 MI−Amodiaquine463MI−136 SRT1720 ● ●●● ●●●●●●●●● ●●●●●● PlasmodiumPlasmodium● inhibition inhibition● at● ●at1● µM1 µM (%) (%)● % inhibition DNMT HDAC ●●● ● ● ● ● ●HDM● ●●●DNMT●●● HMT ● ● AZD1480●AZD1480 HDAC Kinase HDM % inhibitionOther HMT Kinase Other

● ●●●● ●●●●●0●●●●●●●●●●●●●●●●●●●●●●●●● ●● ●● ● ● ENMDAZD1480−2076 ● 0 25 50 75 ●●●● ●●●●●● ●●●●●DNMT●●● ● ● HDAC MI−136 HDM Other 25 50 75 100 plasmodium ●● ●●●●● ●●●●●% inhibition●●●●●●● ● ●●● ●● shortName ● ●● ● CUDCCUDC−907−907CUDC−907AmodiaquineAmodiaquineAmodiaquineSRT1720 SRT1720 1 µM ● ● ● ●●0 ● ●●●●● ●●●●●●●●● ●●●● shortNameshortName25 ● 50 75 100 ●●●0●●●●●●●0●●●●●●●●●●●●●●●●●●●●●0●●●25●●●●●50●●●●75●● ● ● ●●● ● AZD1480 ● ●●● ●●●0 ●●●●● ●●●%●● inhibition●● ●●● ●● ● ● ● ● % inhibition ● ●● 0 0 25 50 75 ●25Plasmodium inhibition at 1 µM50 (%) 75 100 0 25 50 75 ● ●●● ●● ● DNMT CUDCHDAC −907 Amodiaquine SRT1720 HDM 0 25 50 75 HMT Kinase Other ● ●● ●●●●●● Plasmodium inhibition at 1 µM (%) 0 ●●●●●●● ●●●●●●●SAHA●●● ●● ● ●shortName● ● 0 −SAHASAHA 25 50 75 100 101 SAHA −− 0 907 shortNameshortName25 50 75 100 2076 −101101 −SAHASAHA235 0 −907907 25 50 314 75 100 − 20762076 1027 42 −− −− −235 −− 04 507 − 314 6258 −− 1776 1027−1027 −42 −235 − 04 Plasmodium inhibition at 1 µM (%)− 507 463 136 −314 847325 − 6258 − 17761776 − 42 iodo − −04 Plasmodium inhibitionDeazaneplanocin at 1 µM−507 A (%)− 463 − 136 − − 847325 6258 % inhibition − − −− −iodo − Deazaneplanocin− A −463 −136 −847325 −− − SGI DacinostatApicidin AR Belinostat HC Toxin Givinostat CAY10603VorinostatCAY10398M 344 −iodo LMK SRT1720 JIB SGC0946UNC1999 UNC0631UNC0646UNC0638BIX01294PlasmodiumUNC0642UNC0379−−Deazaneplanocin ChaetocininhibitionLLY AMI −at MI1− µM Reversine(%) Go 6983SNS AZ 960 − CX AZD1480Barasertib TG101209FedratinibSGI Pirarubicin GemcitabineGemcitabineSGI QuisinostatQuisinostatPanobinostatPanobinostatDacinostatApicidinTrichostatinTrichostatinAR A BelinostatNexturastatNexturastatHC Toxin A AbexinostatAbexinostatCUDCCUDCPracinostatPracinostatGivinostatPyroxamidePyroxamideCAY10603VorinostatCAY10398M 3444− LMK CoumarinRicolinostatResminostatTubastatinCUDC A A SRT1720JIB EPZ004777SGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC03793− ChaetocinLLY MI MI ReversineGandotinibGandotinibGo 6983SNS HesperadinHesperadinAuroraAurora ALestaurtinib LestaurtinibA Inhibitor InhibitorAZ I 960 I BIBI ZMZM 447439 447439CX AZD1480BarasertibENMDENMDGSK1070916GSK1070916TG101209Fedratinib25SGI50 75Pirarubicin100MitomycinMitomycinAmodiaquineAmodiaquine C C GemcitabineSGI QuisinostatPanobinostatDacinostatApicidinTrichostatinAR A BelinostatNexturastatHC Toxin A AbexinostatCUDC PracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 344 40 LMK CoumarinRicolinostatSAHAResminostatTubastatinCUDC A SRT1720 JIB25 EPZ004777SGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX0129450UNC0642UNC037933 ChaetocinLLY MI MI Reversine75GandotinibGo 6983SNS HesperadinAurora ALestaurtinib InhibitorAZ I960BI ZM100 447439CX AZD1480BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C − conc_nM

101 SAHA SAHA 907 shortName 2076

− SAHA − babesia − 235 −− − 314 delta 1027 SAHA Plasmodium inhibition at 1 µM (%) 507 2076 1776 babesia 42 101 SAHA− 907 04 − 6258 2076 conc_nM − − 101 −− − 907 − − 463 136 847325 − − − − conc_nM 1027 − iodo 235235 − Deazaneplanocin507 A − − 314314 − − 1776 1 µM1 µM − 1027 4242 − −− 0404 − 507 463 136 −− 6258 −1776 1 µM GemcitabineSGI − QuisinostatPanobinostatDacinostatApicidin AR− − Belinostat HC ToxinAbexinostatCUDC PracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 344 LMK RicolinostatResminostatTubastatinCUDCDelta A SRT1720 JIB−− EPZ004777SGC0946UNC1999EPZ005687UNC0631UNC0646UNC0638BIX01294UNC0642UNC0379− ChaetocinLLY− MI− 463MI− 136 ReversineGandotinibGo 6983SNS Hesperadin LestaurtinibAZ 960BI 847325ZM 447439CX− AZD1480BarasertibENMD TG101209FedratinibSGI− PirarubicinMitomycinAmodiaquine C Trichostatin A Nexturastat A 4 iodoiodo Coumarin 3 DeazaneplanocinDeazaneplanocin AA − − Aurora A Inhibitor I − GSK1070916 −− −− GemcitabineGemcitabineSGISGI QuisinostatQuisinostatPanobinostatPanobinostatDacinostatDacinostatApicidinApicidinTrichostatinTrichostatinARAR A ABelinostatBelinostatNexturastatNexturastatHCHC Toxin A Toxin AAbexinostatAbexinostatCUDCCUDCPracinostatPracinostatGivinostatGivinostatPyroxamidePyroxamideCAY10603CAY10603VorinostatVorinostatCAY10398CAY10398MM 344 34444 LMKLMK CoumarinCoumarinRicolinostatRicolinostatResminostatResminostatTubastatinTubastatinCUDCCUDC A A SRT1720SRT1720JIBJIB EPZ004777EPZ004777SGC0946SGC0946UNC1999UNC1999EPZ005687EPZ005687UNC0631UNC0631UNC0646UNC0646UNC0638UNC0638BIX01294BIX01294UNC0642UNC0642UNC0379UNC037933 ChaetocinChaetocinLLYLLY MIMI MIMI ReversineReversineGandotinibGandotinibGoGo 69836983SNSSNS HesperadinHesperadinAurora ALestaurtinib InhibitorAZ I960BI ZM 447439CX AZD1480BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquineAmodiaquine C

DNMT HDAC HDM HMT Kinase Other

SAHA babesia

−

babesia babesia

101 SAHA 907 2076 plasmodium conc_nM − − plasmodium − − 1 µM conc_nM 235 314 conc_nM 1027 42 − 04 507 − 1776 1 µMµM − − − 463 136 847325 6258 − 11 µMµM − iodo Bd Deazaneplanocin A − − − − − % inhibition − GemcitabineSGI QuisinostatPanobinostatDacinostatApicidinTrichostatinAR A BelinostatNexturastatHC Toxin A AbexinostatCUDC PracinostatGivinostatPyroxamideCAY10603VorinostatCAY10398M 344 4 LMK CoumarinRicolinostatResminostatTubastatinCUDC A SRT1720 JIB EPZ004777SGC0946UNC1999−75−EPZ00568750−250UNC06312550UNC064675100UNC0638BIX01294UNC0642UNC03793 ChaetocinLLY MI MI ReversineGandotinibGo 6983SNS HesperadinAurora ALestaurtinib InhibitorAZ I960BI ZM 447439CX AZD1480BarasertibENMD GSK1070916TG101209FedratinibSGI PirarubicinMitomycinAmodiaquine C

DNMT HDAC HDM HMT Kinase Other DNMT HDAC HDM HMT Kinase Other plasmodium plasmodium plasmodium babesia Pf 11 µMµM conc_nM

DNMTDNMTDNMT HDACHDACHDAC HDMHDMHDM %% inhibitioninhibition HMTHMTHMT Kinase Other

0 2525 5050 7575 100 HMT Kinase plasmodium 1 µM %% inhibition inhibition % inhibition 00 2525 5050 7575 0 25 50 75 DNMT HDAC HDM HMT Kinase Other Figure 3. Differential activity of epigenetic inhibitors against B. divergens and P. falciparum. % inhibition (A) Scatterplot comparing25 50 75 100 %inhibition at 1 µM against B. divergens and P. falciparum. Compound names are indicated for compounds with more than 2-fold difference in activity (dotted lines) and more than 50% inhibition at 1 µM against one species (dashed lines). An enlarged scatterplot with labelled compound names is displayed for compounds with ≥75% at 1 µM against both species. (B) Heatmap of compounds with at least 50% inhibition at 1 µM against one species, ordered by the delta activity (% Pf inhibition - % Bd inhibition) and grouped by proposed target category. A B. divergens P. falciparum asexualbabesia babesiaasexual MI−463 MI−463 MI−503 MI−503 1010 UNC1999 UNC1999 ● ● Ricolinostat Ricolinostat GSK343 GSK343 Citarinostat Citarinostat 99 ● ● ● ●

88 SRT1720 SRT1720 pairs BIX01294 pairs BIX01294 SRT2183 SRT2183 a Pair 1 UNC0224 UNC0224 ●a ●Pair 1 7 77 MI−136 a Pair 10 ● MI−136 Vorinostat ● Vorinostat ●a ●Pair 10 MI−503 MI−503 BML−210 a ●aPairPair 11 11 UNC0631 BML −210 UNC0631 ● UNC0646 ● UNC0646 ● a ●aPairPair 12 12 UNC0224● UNC0224● ● BIX01294 ●● BIX01294 UNC0224 ●● 66 UNC0224 ● ● ● ●a ●aPairPair 13 13 UNC0224 ● BIX01294 Belinostat UNC0224 UNC0631 BIX01294 Belinostat UNC0631 a aPairPair 2 2

SALI ● Belinostat ● Belinostat UNC0321 ● Oxamflatin UNC0224 UNC0646 UNC0321 Oxamflatin UNC0224● SALI UNC0646 Pair 3 SALI ● ● ● ●a ●aPair 3 Oxamflatin ● Oxamflatin ● UNC0646 ● ● UNC0646 UNC0224 ● UNC0631 UNC0224 ●AR−42● AR●−42● ●a ●aPairPair 4 4 UNC0321 UNC0321 AR−42 UNC0321 UNC0631 5 AR−42 ● ● aPairPair 5 5 55 HPOB ● UNC0631 HPOB UNC0638● UNC0631 ●a ● ●HPOB UNC0638● UNC0646 ● HPOB UNC0321 BIX01294 ● UNC0321 BIX01294 ● UNC0321 ●a ●aPairPair 6 6 UNC0224 UNC0321 ● UNC0224 UNC0646 UNC1999 ● UNC1999 ● UNC0321● ● UNC0638 UNC0321● ● ●a ●aPairPair 7 7 GSK503 Lestaurtinib Lestaurtinib UNC0321 Lestaurtinib GSK503 Lestaurtinib ●a ●aPairPair 8 8 Go6976 UNC0224 Go6976 UNC0638 Vorinostat Go6976 Vorinostat Go6976 UNC0224 ●a ●aPairPair 9 9 BML−210 BML−210 44 ●● ● ●● ● EPZ004777 EPZ004777 Nexturastat A Nexturastat A Nexturastat A Pinometostat Nexturastat Pinometostat A HPOB HPOB HPOB HPOB ● ● ● ● ● ●

33

0.550 0.660 0.770 0.880 0.990 1.0100 1.1 0.550 0.660 0.770 0.880 0.990 1.0100 1.1 50 60 70 80 90 100 Delta_activityDelta_activity50 (%) 60 70 80 90 100 Delta activity (%)

B C O O S N H C H N N S N N N N O O N N C N N B. divergens B. divergens P. f a l c i p a r u m N Compound % inhibition at 1 µM Compound % inhibition % inhibition ±SEM at 1 µM ±SEM at 1 µM ±SEM N UNC1999 89.2% ± 3.3 Belinostat 82.4% ± 4.8 87.0% ± 2.7 GSK503 24.0% ± 19.7 Oxamflatin 2.4% ± 4.2 1.8% ± 17.4 GSK343 9.6% ± 14.8 Figure 4. Activity cliff analysis. (A) Scatterplot of 19 activity cliff pairs with >50% delta activity and >80% structural similarity, grouped by species. Compound pairs that display an activity cliff in both species are indicated in matching colors. (B-C) Examples of activity cliff pairs with respective chemical structures and in vitro activity at 1 µM. A

B. divergensbabesia P. falciparumasexual 31000 BIX01294 ● ● 1700017000 UNC0224 ● UNC0631 BIX01294 ● UNC0224 UNC0646 UNC0224 UNC0646 UNC0224 UNC0224 1600016000 2900029000 ● ● UNC0631 UNC0224 pairs 1500015000 ● Pair 1 ● Pair 2

SALI ● Pair 3 2700027000 ● Pair 4 SALI ● Pair 5 1400014000

UNC0638 UNC0224 ● UNC0638 1300013000 2500025000 UNC0224 ● UNC0642 UNC0642 UNC0224 ● UNC0224 ● 1200012000 2020 40 60 100 200 300 400 500 40 60 EC50 fold change100 200 300 400 500 EC50 fold change B C

N NN NN NN

R NN N NN R R NN F F

B. divergens B. divergens P. falciparum B.divergens EC50 / Compound Compound EC50 ±SEM EC50 ±SEM EC50 ±SEM P.falciparum EC50 UNC0631 43.4 nM ± 0.1 UNC0642 466.6 nM ± 1.5 19.2 nM ± 10.4 24.3 x5 UNC0646 199.8 nM ± 0.8 BIX01294 252.0 nM ± 0.8 10.5 nM ± 3.6 24 BIX01294 252.0 nM ± 0.8 375.5 nM ± 1.4 21.6 nM ± 2.0 17.3 x2 UNC0638 UNC0638 375.5 nM ± 1.4 UNC0631 43.4 nM ± 0.1 28.5 nM ± 5.9 1.5 UNC0642 466.6 nM ± 1.5 UNC0646 199.8 nM ± 0.8 140.1 nM ± 3.8 1.4 x10 UNC0224 1-10 µM UNC0224 1-10 µM 1-10 µM 1

Figure 5. HMT inhibitors with a diaminoquinazoline backbone. (A) Pairs of diaminoquinazoline compounds with >60% similarity and >50% delta activity at 1 µM. (B) Activity of compounds with a diaminoquinazoline backbone against Babesia divergens. (C) Changes in chemical structure that confer differential activity against both species. 101010 µM µMµM 1 µM 1 µM ZM 39923 ● ● ● ZM 39923 Valproic Acid ● ● ● Valproic Acid Tasquinimod ● ● ● Tasquinimod Splitomicin ● ● ● Splitomicin SMI−4a ● ● ● SMI−4a SGC2085 ● ● ● SGC2085 Santacruzamate A ● ● ● Santacruzamate A RG−108 ● ● ● RG−108 Phenformin ● ● ● Phenformin PFI−1 ● ● ● PFI−1 ORY−1001 ● ● ● ORY−1001 Octyl−alpha−ketoglutarate ● ● ● Octyl−alpha−ketoglutarate Oclacitinib ● ● ● Oclacitinib NU1025 ● ● ● NU1025 N−Oxalylglycine ● ● ● N−Oxalylglycine MS049 ● ● ● MS049 MK−5108 ● ● ● MK−5108 MI−503 ● ● ● MI−503 Metformin ● ● ● Metformin ME0328 ● ● ● ME0328 KD 5170 ● ● ● KD 5170 IOX2 ● ● ● IOX2 IOX1 ● ● ● IOX1 INO−1001 ● ● ● INO−1001 HPI−4 ● ● ● HPI−4 HNHA ● ● ● HNHA GSK−LSD1 ● ● ● GSK−LSD1 GSK−J1 ● ● ● GSK−J1 F−Amidine ● ● ● F−Amidine ETC−1002 ● ● ● ETC−1002 EPZ015666 ● ● ● EPZ015666 Ellagic Acid ● ● ● Ellagic Acid E7449 ● ● ● E7449 Divalproex ● ● ● Divalproex Daphnetin ● ● ● Daphnetin Daminozide ● ● ● Daminozide Curcumol ● ● ● Curcumol CAY10669 ● ● ● CAY10669 C646 ● ● ● C646 Butyrolactone 3 ● ● ● Butyrolactone 3 Butyrate ● ● ● Butyrate BG45 ● ● ● BG45 Azacitidine ● ● ● Azacitidine AICAR ● ● ● AICAR AG−490 ● ● ● AG−490 5−Methylcytidine ● ● ● 5−Methylcytidine 2,4−Pyridinedicarboxylate ● ● ● 2,4−Pyridinedicarboxylate 2,3,5−triacetyl−5−Azacytidine ● ● ● 2,3,5−triacetyl−5−Azacytidine (+)−Abscisic Acid ● ● ● (+)−Abscisic Acid Nicotinamide ● ● ● Nicotinamide Selisistat ● ● ● Selisistat GSK2879552 ● ● ● GSK2879552 Veliparib ● ● ● Veliparib Droxinostat ● ● ● Droxinostat Daptomycin ● ● ● Daptomycin Anacardic Acid ● ● ● Anacardic Acid 1−Naphthoic Acid ● ● ● 1−Naphthoic Acid GSK−J2 ● ● ● GSK−J2 Sirtinol ● ● ● Sirtinol NVP−TNKS656 ● ● ● NVP−TNKS656 Salermide ● ● ● Salermide PFI−3 ● ● ● PFI−3 A−769662 ● ● ● A−769662 AG−14361 ● ● ● AG−14361 Phenylbutyrate ● ● ● Phenylbutyrate a−Hydroxyglutarate ● ● ● a−Hydroxyglutarate FG−2216 ● ● ● FG−2216 SIRT1/2 Inhibitor IV ● ● ● SIRT1/2 Inhibitor IV Delphinidin ● ● ● Delphinidin CPTH2 ● ● ● CPTH2 AGK7 ● ● ● AGK7 Daprodustat ● ● ● Daprodustat 5−Methyl−2−deoxycytidine ● ● ● 5−Methyl−2−deoxycytidine Entacapone ● ● ● Entacapone Tofacitinib ● ● ● Tofacitinib Picolinamide ● ● ● Picolinamide Benzamide ● ● ● Benzamide BGP−15 2HCl ● ● ● BGP−15 2HCl UNC0321 ● ● ● UNC0321 SAH ● ● ● SAH MG149 ● ● ● MG149 Quercetin ● ● ● Quercetin BRD73954 ● ● ● BRD73954 Roxadustat ● ● ● Roxadustat DMOG ● ● ● DMOG Iniparib ● ● ● Iniparib Niraparib ● ● ● Niraparib CI−994 ● ● ● CI−994 2−PCPA ● ● ● 2−PCPA UNC669 ● ● ● UNC669 Fisetin ● ● ● Fisetin (−)−Parthenolide ● ● ● (−)−Parthenolide EPZ020411 ● ● ● EPZ020411 BML−210 ● ● ● BML−210 Zebularine ● ● ● Zebularine Thioguanine ● ● ● Thioguanine ITSA−1 ● ● ● ITSA−1 PHA−680632 ● ● ● PHA−680632 Curcumin ● ● ● Curcumin NMS−P118 ● ● ● NMS−P118 2−Methoxyestradiol ● ● ● 2−Methoxyestradiol CPI−455 ● ● ● CPI−455 SRT2183 ● ● ● SRT2183 UPF 1069 ● ● ● UPF 1069 3,3−Diindolylmethane ● ● ● 3,3−Diindolylmethane Baricitinib ● ● ● Baricitinib SAM ● ● ● SAM PFI−2 ● ● ● PFI−2 Procainamide ● ● ● Procainamide Pimelic Diphenylamide 106 ● ● ● Pimelic Diphenylamide 106 UNC3866 ● ● ● UNC3866 Decitabine ● ● ● Decitabine Resveratrol ● ● ● Resveratrol Cl−Amidine ● ● ● Cl−Amidine MK−8617 ● ● ● MK−8617 RG2833 ● ● ● RG2833 Clevudine ● ● ● Clevudine AMI−1 ● ● ● AMI−1 I−CBP112 ● ● ● I−CBP112 WDR5−0103 ● ● ● WDR5−0103 6−Thioguanine ● ● ● 6−Thioguanine I−BET762 ● ● ● I−BET762 Epigallocatechin Gallate ● ● ● Epigallocatechin Gallate Olaparib ● ● ● Olaparib A−966492 ● ● ● A−966492 Isoliquiritigenin ● ● ● Isoliquiritigenin BI−7273 ● ● ● BI−7273 OG−L002 ● ● ● OG−L002 Ruxolitinib ● ● ● Ruxolitinib 2−hexyl−4−Pentynoic Acid ● ● ● 2−hexyl−4−Pentynoic Acid AZD1208 ● ● ● AZD1208 UNC1215 ● ● ● UNC1215 GSK591 ● ● ● GSK591 Filgotinib ● ● ● Filgotinib Lomeguatrib ● ● ● Lomeguatrib JGB1741 ● ● ● JGB1741 Lificiguat ● ● ● Lificiguat AZD2461 ● ● ● AZD2461 Piceatannol ● ● ● Piceatannol Chidamide ● ● ● Chidamide Suramin ● ● ● Suramin WP1066 ● ● ● WP1066 MS023 ● ● ● MS023 AMG−900 ● ● ● AMG−900 MC 1568 ● ● ● MC 1568 Remodelin ● ● ● Remodelin Mirin ● ● ● Mirin MM−102 ● ● ● MM−102 PX−478 ●● ● ● PX−478 Mivebresib ●● ● ● Mivebresib Peficitinib ●● ● ● Peficitinib MLN8054 ●● ● ● MLN8054 CPI−203 ●● ● ● CPI−203 PJ34 HCl ●● ● ● PJ34 HCl OICR−9429 ●● ● ● OICR−9429 MK−8745 ●● ● ● MK−8745 CPI−1205 ●● ● ● CPI−1205 I−BET151 ●● ● ● I−BET151 PCI 34051 ●● ● ● PCI 34051 Fasudil ●● ● ● conc_nMFasudil compound conc_nM Alisertib ●● ● ● Alisertib ●● ● ● 4SC−202 ●4SC10− 202µM ● 10 µM AGK2 ●● ● ● AGK2 ●● ● ● Entinostat ●Entinostat1 µM ● 1 µM compound MS436 ●● ● ● MS436 HLCL−61 ●● ● ● HLCL−61 SirReal2 ●● ● ● SirReal2 RGFP966 ●● ● ● RGFP966 GSK2801 ●● ● ● GSK2801 Garcinol ●● ● ● Garcinol PNU−74654 ●● ● ● PNU−74654 Salvianolic acid B ●● ● ● Salvianolic acid B SGC707 ●● ● ● SGC707 I−BET726 ●● ● ● I−BET726 3−Deazaneplanocin A ●● ● ● 3−Deazaneplanocin A Phthalazinone pyrazole ●● ● ● Phthalazinone pyrazole TMP269 ●● ● ● TMP269 Amodiaquine ●● ● ● Amodiaquine CPI−169 ●● ● ● CPI−169 LW 6 ●● ● ● LW 6 SGC−CBP30 ●● ● ● SGC−CBP30 GSK4112 ●● ● ● GSK4112 Tubacin ●● ● ● Tubacin AK−7 ●● ● ● AK−7 KC7F2 ●● ● ● KC7F2 TMP195 ●● ● ● TMP195 Sotrastaurin ●● ● ● Sotrastaurin Tenovin−1 ●● ● ● Tenovin−1 FLLL32 ●● ● ● FLLL32 Methylstat ●● ● ● Methylstat CAY10591 ●● ● ● CAY10591 (−)−JQ1 ●● ● ● (−)−JQ1 EED226 ●● ● ● EED226 SRT3025 ●● ● ● SRT3025 CUDC−907 ●● ● ● CUDC−907 CPI−360 ●● ● ● CPI−360 HPOB ●● ● ● HPOB XL019 ●● ● ● XL019 CCG−100602 ●● ● ● CCG−100602 AZ6102 ●● ● ● AZ6102 RSC−133 ●● ● ● RSC−133 OTX015 ●● ● ● OTX015 (+)−JQ1 ●● ● ● (+)−JQ1 Decernotinib ●● ● ● Decernotinib Tubastatin A ●● ● ● Tubastatin A SRT2104 ●● ● ● SRT2104 MI−nc ● ● ● ● MI−nc Neplanocin A ● ● ● ● Neplanocin A Enzastaurin ● ● ● ● Enzastaurin PF−CBP1 ● ● ● ● PF−CBP1 Pinometostat ● ● ● ● Pinometostat AZD5153 ● ● ● ● AZD5153 UNC0224 ● ● ● ● UNC0224 TAK−901 ● ● ● ● TAK−901 MI−3 ● ● ● ● MI−3 KW−2449 ● ● ● ● KW−2449 Rucaparib ● ● ● ● Rucaparib Cerdulatinib ● ● ● ● Cerdulatinib CPI−0610 ● ● ● ● CPI−0610 RVX−208 ● ● ● ● RVX−208 SRT1720 ● ● ● ● SRT1720 MI−2 ● ● ● ● MI−2 Citarinostat ● ● ● ● Citarinostat GSK6853 ● ● ● ● GSK6853 JNJ−7706621 ● ● ● ● JNJ−7706621 A−366 ● ● ● ● A−366 GSK343 ● ● ● ● GSK343 Danusertib ● ● ● ● Danusertib Gemcitabine ● ● ● ● Gemcitabine I−BRD9 ● ● ● ● I−BRD9 Mocetinostat ● ● ● ● Mocetinostat Nullscript ● ● ● ● Nullscript MI−463 ● ● ● ● MI−463 MI−136 ● ● ● ● MI−136 A−196 ● ● ● ● A−196 Go6976 ● ● ● ● Go6976 CEP−33779 ● ● ● ● CEP−33779 AZD1480 ● ● ● ● AZD1480 CPI−637 ● ● ● ● CPI−637 Tozasertib ● ● ● ● Tozasertib GSK503 ● ● ● ● GSK503 WHI−P154 ● ● ● ● WHI−P154 Bromosporine ● ● ● ● Bromosporine Thiomyristoyl ● ● ● ● Thiomyristoyl PFI−4 ● ● ● ● PFI−4 CBHA ● ● ● ● CBHA EI1 ● ● ● ● EI1 LMK−235 ● ● ● ● LMK−235 Barasertib ● ● ● ● Barasertib HTH−01−015 ● ● ● ● HTH−01−015 Chaetocin ● ● ● ● Chaetocin Ricolinostat ● ● ● ● Ricolinostat GSK−J4 ● ● ● ● GSK−J4 Pyroxamide ● ● ● ● Pyroxamide Momelotinib ● ● ● ● Momelotinib Pacritinib ● ● ● ● Pacritinib OF−1 ● ● ● ● OF−1 TG101209 ● ● ● ● TG101209 Fedratinib ● ● ● ● Fedratinib Bisindolylmaleimide IX ● ● ● ● Bisindolylmaleimide IX ENMD−2076 ● ● ● ● ENMD−2076 G007−LK ● ● ● ● G007−LK M 344 ● ● ● ● M 344 Resminostat ● ● ● ● Resminostat Sinefungin ● ● ● ● Sinefungin Scriptaid ● ● ● ● Scriptaid 4−iodo−SAHA ● ● ● ● 4−iodo−SAHA CYC116 ● ● ● ● CYC116 CAY10398 ● ● ● ● CAY10398 AT9283 ● ● ● ● AT9283 GSK1070916 ● ● ● ● GSK1070916 ZM 447439 ● ● ● ● ZM 447439 WZ4003 ● ● ● ● WZ4003 GSK126 ● ● ● ● GSK126 EPZ005687 ● ● ● ● EPZ005687 Etoposide ● ● ● ● Etoposide BMS−911543 ● ● ● ● BMS−911543 ML324 ● ● ● ● ML324 Coumarin−SAHA ● ● ● ● Coumarin−SAHA SP2509 ● ● ● ● SP2509 NVP−BSK805 ● ● ● ● NVP−BSK805 Nexturastat A ● ● ● ● Nexturastat A Vorinostat ● ● ● ● Vorinostat CUDC−101 ● ● ● ● CUDC−101 Oxamflatin ● ● ● ● Oxamflatin Tenovin−6 ● ● ● ● Tenovin−6 EPZ004777 ● ● ● ● EPZ004777 Aurora A Inhibitor I ● ● ● ● Aurora A Inhibitor I Reversine ● ● ● ● Reversine BRD4770 ● ● ● ● BRD4770 SGC0946 ● ● ● ● SGC0946 Pracinostat ● ● ● ● Pracinostat Go 6983 ● ● ● ● Go 6983 Apicidin ● ● ● ● Apicidin SNS−314 ● ● ● ● SNS−314 Givinostat ● ● ● ● Givinostat Belinostat ● ● ● ● Belinostat HC Toxin ● ● ● ● HC Toxin SGI−1776 ● ● ● ● SGI−1776 Lestaurtinib ● ● ● ● Lestaurtinib Trichostatin A ● ● ● ● Trichostatin A Panobinostat ● ● ● ● Panobinostat Dacinostat ● ● ● ● Dacinostat UNC0638 ● ● ● ● UNC0638 BI−847325 ● ● ● ● BI−847325 UNC0646 ● ● ● ● UNC0646 UNC0642 ● ● ● ● UNC0642 Quisinostat ● ● ● ● Quisinostat AR−42 ● ● ● ● AR−42 Abexinostat ● ● ● ● Abexinostat LLY−507 ● ● ● ● LLY−507 CX−6258 ● ● ● ● CX−6258 Mitomycin C ● ● ● ● Mitomycin C CAY10603 ● ● ● ● CAY10603 AZ 960 ● ● ● ● AZ 960 UNC0631 ● ● ● ● UNC0631 UNC1999 ● ● ● ● UNC1999 Hesperadin ● ● ● ● Hesperadin Pirarubicin ● ● ● ● Pirarubicin Gandotinib ● ● ● ● Gandotinib BIX01294 ● ● ● ● BIX01294 SGI−1027 ● ● ● ● SGI−1027 UNC0379 ● ● ● ● UNC0379 JIB−04 ● ● ● ● JIB−04 0 2525 5050 7575 100100 0 0 25 25 50 50 75 75 100 100 0 25 50 75 100%% inhibition inhibition0 25 50 75 100 % inhibition Figure S1. Mean Percent Inhibition of all 324 compounds against B. divergens at 10 μM and 1 μM. The dotted and dashed lines indicate 50% and 90% inhibition, respectively. Compounds are ordered by increasing activity at 10 μM. Error bars are standard error of n=3. 0.8

0.6

0.4

0.2

Analysis Y Analysis 0

-0.2 Neighbor Neighbor

-0.4

-0.6

-0.8

-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 Neighbor Analysis X

Target Category HMT HAT Other HDM HDAC PARP DNMT Kinase Histone Reader

Figure S2. Structural feature similarity landscape. Compounds with >80% structural similarity were grouped in Datawarrior (SkelSphere). Color indicates reported epigenetic process targeted in higher eukaryotes. 100

75

50

1001.0 800.8 600.6 400.4 200.2 0 0.0 pfmax 25 % Inhibition of most potent compound in each pair Delta (%) activity 1 Delta atµM 1.0 ● ● ● ● ● ● ● ● ●

0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 20 40 60 80 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Similarity (%) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Figure S3. Activity cliff analysis for Babesia divergens at 1 μM. Scatterplot with each dot ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.8 ● ● ● ● ● representing a pair of compounds in the library. Compound pairs of interest have ≥50% delta ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● activity (dashed line) and ≥80% structural similarity (dotted● line). ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 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● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● similarity ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 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● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 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● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.0

1.00 0.75 0.50 0.25 0.00 delta activity delta Pf % inhibition Pf %inhibition at Compound Compound at 1 µM ±SEM 1 µM ±SEM Cl MI-463 93.6% ± 1.1 Ricolinostat 51.1% ± 4.9 MI-136 91.6% ± 3.2 Citarinostat -0.7% ± 29.9 C MI-503 -10.7% ± 11.7

H Bd %inhibition Pf %inhibition NH2 Compound H at 1 µM ±SEM at 1 µM ±SEM N OH HN Vorinostat 68.1% ± 7.8 94.5% ± 1.7

BML-210 0.4% ± 4.4 -12.5% ± 4.0 O

Bd %inhibition Compound at 1 µM ±SEM Bd %inhibition Pf %inhibition Compound at 1 µM ±SEM at 1 µM ±SEM EPZ004777 85.5% ± 3.5 Lestaurtinib 96.6% ± 0.7 82.5% ± 4.3 Pinometostat 15.0% ± 20.0 Go6976 6.7% ± 6.3 5.5% ± 1.8 NC O HO N C C Bd %inhibition Pf %inhibition Compound Pf %inhibition at 1 µM ±SEM at 1 µM ±SEM Compound at 1 µM ±SEM AR-42 93.4% ± 1.7 97.7% ± 0.3 O SRT1720 98.1% ± 1.9 Nexturastat 66.6% ± 7.8 73.7% ± 3.2 N A H SRT2183 5.9% ± 4.1 H N N HPOB 5.0% ± 3.0 13.8% ± 19.7 O

Figure S4. Structural representation of the remaining activity cliff pairs that are displayed in figure 4A. N NN NN NN

NN N NN NN F F

P. falciparum Compound EC50 (±SEM)

BIX01294 10.5 nM ± 3.6

UNC0642 19.2 nM ± 10.4

UNC0638 21.6 nM ± 2.0

UNC0631 28.5 nM ± 5.9

UNC0646 140.1 nM ± 3.8

UNC0224 1-10 µM

Figure S5. Activity of HMT inhibitors with a diaminoquinazoline backbone against P. falciparum. Table ST1. EC50 Activity of epigenetic inhibitors tested grouped by target category. Percentage of active compounds is indicated in brackets (n=2-3).

Table ST2. EC90 Activity of epigenetic inhibitors tested grouped by target category. Percentage of active compounds is indicated in brackets (n=2-3).