Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action
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Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition
Published OnlineFirst September 23, 2016; DOI: 10.1158/1078-0432.CCR-16-0620 Biology of Human Tumors Clinical Cancer Research Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin- Dependent Kinase 2 and AKT Inhibition George Au-Yeung1,2, Franziska Lang1, Walid J. Azar1, Chris Mitchell1, Kate E. Jarman3, Kurt Lackovic3,4, Diar Aziz5, Carleen Cullinane1,6, Richard B. Pearson1,2,7, Linda Mileshkin2,8, Danny Rischin2,8, Alison M. Karst9, Ronny Drapkin10, Dariush Etemadmoghadam1,2,5, and David D.L. Bowtell1,2,7,11 Abstract Purpose: Cyclin E1 (CCNE1) amplification is associated with Results: We validate CDK2 as a therapeutic target by demon- primary treatment resistance and poor outcome in high-grade strating selective sensitivity to gene suppression. However, we found serous ovarian cancer (HGSC). Here, we explore approaches to that dinaciclib did not trigger amplicon-dependent sensitivity in a target CCNE1-amplified cancers and potential strategies to over- panel of HGSC cell lines. A high-throughput compound screen come resistance to targeted agents. identified synergistic combinations in CCNE1-amplified HGSC, Experimental Design: To examine dependency on CDK2 in including dinaciclib and AKT inhibitors. Analysis of genomic data CCNE1-amplified HGSC, we utilized siRNA and conditional from TCGA demonstrated coamplification of CCNE1 and AKT2. shRNA gene suppression, and chemical inhibition using dina- Overexpression of Cyclin E1 and AKT isoforms, in addition to ciclib, a small-molecule CDK2 inhibitor. High-throughput mutant TP53, imparted malignant characteristics in untransformed compound screening was used to identify selective synergistic fallopian tube secretory cells, the dominant site of origin of HGSC. -
TAK1 Mediates Convergence of Cellular Signals for Death and Survival
Apoptosis (2019) 24:3–20 https://doi.org/10.1007/s10495-018-1490-7 REVIEW TAK1 mediates convergence of cellular signals for death and survival Sabreena Aashaq1 · Asiya Batool1 · Khurshid I. Andrabi1 Published online: 4 October 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract TGF-β activated kinase 1, a MAPK kinase kinase family serine threonine kinase has been implicated in regulating diverse range of cellular processes that include embryonic development, differentiation, autophagy, apoptosis and cell survival. TAK1 along with its binding partners TAB1, TAB2 and TAB3 displays a complex pattern of regulation that includes serious crosstalk with major signaling pathways including the C-Jun N-terminal kinase (JNK), p38 MAPK, and I-kappa B kinase complex (IKK) involved in establishing cellular commitments for death and survival. This review also highlights how TAK1 orchestrates regulation of energy homeostasis via AMPK and its emerging role in influencing mTORC1 pathway to regulate death or survival in tandem. Keywords Apoptosis · Autophagy · Cytokine · Inflammatory · Smad TAK1, a multifunctional kinase regulate a wide array of downstream cellular responses [2, 7, 8]. Various branches of MAP kinase pathways including Transforming growth factor-β is a versatile cytokine, regu- the extracellular signal regulated kinase (Erk) ½ [3, 9], p38 lating a wide variety of intracellular signaling pathways. MAPK [10, 11], c-Jun N-Terminal kinase (JNK) [12, 13], The Smad dependent signaling pathway is conventionally phosphatidylinositol-3-kinase/AKT pathway [14, 15] and acknowledged as the traditional pathway promoted by TGF- Rho-like GTPase [16, 17] signaling pathways are included β1 [1]. However, the Smad dependent signaling pathway among the Smad independent pathways. -
Map2k1 and Map2k2 Genes Contribute to the Normal Development of Syncytiotrophoblasts During Placentation
RESEARCH ARTICLE 1363 Development 136, 1363-1374 (2009) doi:10.1242/dev.031872 Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation Valérie Nadeau*, Stéphanie Guillemette*, Louis-François Bélanger, Olivier Jacob, Sophie Roy and Jean Charron† The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. In the mouse, loss of Map2k1 function causes embryonic lethality, whereas Map2k2 mutants survive with a normal lifespan, suggesting that Map2k1 masks the phenotype due to the Map2k2 mutation. To uncover the specific function of MAP2K2 and the threshold requirement of MAP2K proteins during embryo formation, we have successively ablated the Map2k gene functions. We report here that Map2k2 haploinsufficiency affects the normal development of placenta in the absence of one Map2k1 allele. Most Map2k1+/–Map2k2+/– embryos die during gestation because of placenta defects restricted to extra-embryonic tissues. The impaired viability of Map2k1+/–Map2k2+/– embryos can be rescued when the Map2k1 deletion is restricted to the embryonic tissues. The severity of the placenta phenotype is dependent on the number of Map2k mutant alleles, the deletion of the Map2k1 allele being more deleterious. Moreover, the deletion of one or both Map2k2 alleles in the context of one null Map2k1 allele leads to the formation of multinucleated trophoblast giant (MTG) cells. Genetic experiments indicate that these structures are derived from Gcm1-expressing syncytiotrophoblasts (SynT), which are affected in their ability to form the uniform SynT layer II lining the maternal sinuses. Thus, even though Map2k1 plays a predominant role, these results enlighten the function of Map2k2 in placenta development. -
The CDK4/6 Inhibitor LY2835219 Has Potent Activity in Combination with Mtor Inhibitor in Head and Neck Squamous Cell Carcinoma
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 12 The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma Bo Mi Ku1,*, Seong Yoon Yi3,*, Jiae Koh1, Yeon-Hee Bae1, Jong-Mu Sun2, Se-hoon Lee2, Jin Seok Ahn2, Keunchil Park2, Myung-Ju Ahn2 1 Samsung Biomedical Research Institute, Seoul, Korea 2 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Division of Hematology-Oncology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea *These authors contributed equally to this work Correspondence to: Myung-Ju Ahn, e-mail: [email protected] Keywords: head and neck cancer, CDK4/6 inhibitor, mTOR, cell cycle, targeted therapy Received: September 15, 2015 Accepted: January 23, 2016 Published: February 21, 2016 ABSTRACT Deletion of CDKN2A (p16) or amplification ofCCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin- dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. -
Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach
www.nature.com/scientificreports OPEN Identifcation of candidate repurposable drugs to combat COVID‑19 using a signature‑based approach Sinead M. O’Donovan1,10, Ali Imami1,10, Hunter Eby1, Nicholas D. Henkel1, Justin Fortune Creeden1, Sophie Asah1, Xiaolu Zhang1, Xiaojun Wu1, Rawan Alnafsah1, R. Travis Taylor2, James Reigle3,4, Alexander Thorman6, Behrouz Shamsaei4, Jarek Meller4,5,6,7,8 & Robert E. McCullumsmith1,9* The COVID‑19 pandemic caused by the novel SARS‑CoV‑2 is more contagious than other coronaviruses and has higher rates of mortality than infuenza. Identifcation of efective therapeutics is a crucial tool to treat those infected with SARS‑CoV‑2 and limit the spread of this novel disease globally. We deployed a bioinformatics workfow to identify candidate drugs for the treatment of COVID‑19. Using an “omics” repository, the Library of Integrated Network‑Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID‑19 drugs and publicly available SARS‑CoV‑2 infected cell lines to identify novel therapeutics. We identifed a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID‑19, the remaining 12 have antiviral properties and 6 have antiviral efcacy against coronaviruses specifcally, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug fndings are discordant with (i.e., reverse) SARS‑CoV‑2 transcriptome signatures generated in vitro, and a subset are also identifed in transcriptome signatures generated from COVID‑19 patient samples, like the MEK inhibitor selumetinib. Overall, our fndings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID‑19 and identify promising novel targets that are worthy of further investigation. -
A Novel CDK9 Inhibitor Increases the Efficacy of Venetoclax (ABT-199) in Multiple Models of Hematologic Malignancies
Leukemia (2020) 34:1646–1657 https://doi.org/10.1038/s41375-019-0652-0 ARTICLE Molecular targets for therapy A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies 1 1 2,3 4 1 5 6 Darren C. Phillips ● Sha Jin ● Gareth P. Gregory ● Qi Zhang ● John Xue ● Xiaoxian Zhao ● Jun Chen ● 1 1 1 1 1 1 Yunsong Tong ● Haichao Zhang ● Morey Smith ● Stephen K. Tahir ● Rick F. Clark ● Thomas D. Penning ● 2,7 3 5 1 4 2,7 Jennifer R. Devlin ● Jake Shortt ● Eric D. Hsi ● Daniel H. Albert ● Marina Konopleva ● Ricky W. Johnstone ● 8 1 Joel D. Leverson ● Andrew J. Souers Received: 27 November 2018 / Revised: 18 October 2019 / Accepted: 13 November 2019 / Published online: 11 December 2019 © The Author(s) 2019 Abstract MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles 1234567890();,: 1234567890();,: that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1- dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. -
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma
CD-13-0617_PAP.indd Page OF1 19/11/13 9:36 PM user-f028 /Books-Arts/JOURNAL-Cancer%20Discovery/01-JAN-Issue-2014/PAP Published OnlineFirst November 21, 2013; DOI: 10.1158/2159-8290.CD-13-0617 RESEARCH ARTICLE The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma Eliezer M. Van Allen 1 , 3 , Nikhil Wagle 1 , 3 , Antje Sucker 5 , 6 , Daniel J. Treacy 1 , Cory M. Johannessen 3 , Eva M. Goetz 1 , Chelsea S. Place 1 , 3 , Amaro Taylor-Weiner 3 , Steven Whittaker 3 , Gregory V. Kryukov 3 , Eran Hodis 1 , 3,4 , Mara Rosenberg 3 , Aaron McKenna 3 , 15 , Kristian Cibulskis 3 , Deborah Farlow 3 , Lisa Zimmer 5 , 6 , Uwe Hillen 5 , 6 , Ralf Gutzmer 8 , Simone M. Goldinger 16 , Selma Ugurel 9 , Helen J. Gogas 17 , Friederike Egberts 10 , Carola Berking 6 , 11 , Uwe Trefzer 6 , 12 , Carmen Loquai 6 , 13 , Benjamin Weide 6 , 14 , Jessica C. Hassel 6 , 7 , Stacey B. Gabriel 3 , Scott L. Carter 3 , Gad Getz 2 , 3 , Levi A. Garraway 1 , 3 , and Dirk Schadendorf 5 , 6 on behalf of the Dermatologic Cooperative Oncology Group of Germany (DeCOG) Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. CD-13-0617_PAP.indd Page OF2 19/11/13 9:36 PM user-f028 /Books-Arts/JOURNAL-Cancer%20Discovery/01-JAN-Issue-2014/PAP Published OnlineFirst November 21, 2013; DOI: 10.1158/2159-8290.CD-13-0617 ABSTRACT Most patients with BRAF V600 -mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. -
Profiling Data
Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8 -
High Expression of LINC01268 Is Positively Associated with Hepatocellular Carcinoma Progression Via Regulating MAP3K7
OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH High Expression of LINC01268 is Positively Associated with Hepatocellular Carcinoma Progression via Regulating MAP3K7 This article was published in the following Dove Press journal: OncoTargets and Therapy Xiuli Jin,1 Weixin Fu,2 Dan Li,1 Objective: As one of the most common neoplastic diseases, hepatocellular carcinoma Ningning Wang,1 Jiayu Chen,1 (HCC) has a high morbidity and mortality, which seriously threatens human health and Zilu Zeng,1 Jiaqi Guo,1 Hao places a heavy burden on society and medical care. At present, effective early diagnosis, Liu,3 Xinping Zhong,3 Hu prognosis and treatment of HCC are limited. Altered gene expression patterns of lncRNA are Peng,4 Xin Yu,5 Jing Sun,1 associated with the occurrence, development and prognosis of various malignancies, includ- ing HCC. The aim of this study was to investigate the correlation between the expression of Xinhe Zhang,1 Xue Wang,1 LINC01268 and HCC, and to elucidate the potential underlying molecular mechanism. Beibei Xu,1 Yingbo Lin,6 4 Methods: Expression level and localization of LINC01268 in human liver cancer cells and Jianping Liu, Claudia HCC tissues were investigated using RT-qPCR and fluorescent in situ hybridization (FISH), 7 1 Kutter, Yiling Li respectively. Correlation of expression levels of LINC01268 and MAP3K7 with differentia- 1Department of Gastroenterology, First tion and poor overall patient survival of HCC were analyzed using in house collected and AffiliatedHospital of China Medical publicly available HCC tissue data. RT-qPCR and Western blot were applied to inspect the University, Shenyang, 110001, People’s Republic of China; 2Science Experiment effects of depletion and overexpression of LINC01268 on MAP3K7 expression. -
Cyclacel's CYC065 CDK Inhibitor Demonstrates Synergy With
Cyclacel’s CYC065 CDK Inhibitor Demonstrates Synergy With Venetoclax By Dual Targeting Of Chronic Lymphocytic Leukemia April 17, 2018 Suppression of both BCl-2 and Mcl-1 anti-apoptotic proteins is a novel strategy in CLL BERKELEY HEIGHTS, N.J., April 17, 2018 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) ("Cyclacel" or the "Company"), a biopharmaceutical company developing oral therapies that target various phases of cell cycle control for the treatment of cancer and other serious disorders, today announced the presentation by investigators led by William Plunkett, PhD, Professor and Deputy Chair, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, of preclinical data demonstrating strong synergy between Cyclacel’s CDK2/9 inhibitor, CYC065, and the Bcl-2 inhibitor, venetoclax (ABT-199, AbbVie) in chronic lymphocytic leukemia (CLL) samples obtained from patients. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting being held April 14-18, 2018 in Chicago, Illinois. “The MD Anderson data show that the combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions. In addition, the combination was active in two CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis,” said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. “Last weekend during the same AACR conference, we reported that CYC065 durably suppresses Mcl-1, a member of the Bcl-2 family of survival proteins, in patients with advanced solid tumors1. -
Coordinate Phosphorylation of Multiple Residues on Single AKT1 and AKT2 Molecules
Oncogene (2014) 33, 3463–3472 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc ORIGINAL ARTICLE Coordinate phosphorylation of multiple residues on single AKT1 and AKT2 molecules H Guo1,6, M Gao1,6,YLu1, J Liang1, PL Lorenzi2, S Bai3, DH Hawke4,JLi1, T Dogruluk5, KL Scott5, E Jonasch3, GB Mills1 and Z Ding1 Aberrant AKT activation is prevalent across multiple human cancer lineages providing an important new target for therapy. Twenty- two independent phosphorylation sites have been identified on specific AKT isoforms likely contributing to differential isoform regulation. However, the mechanisms regulating phosphorylation of individual AKT isoform molecules have not been elucidated because of the lack of robust approaches able to assess phosphorylation of multiple sites on a single AKT molecule. Using a nanofluidic proteomic immunoassay (NIA), consisting of isoelectric focusing followed by sensitive chemiluminescence detection, we demonstrate that under basal and ligand-induced conditions that the pattern of phosphorylation events is markedly different between AKT1 and AKT2. Indeed, there are at least 12 AKT1 peaks and at least 5 AKT2 peaks consistent with complex combinations of phosphorylation of different sites on individual AKT molecules. Following insulin stimulation, AKT1 was phosphorylated at Thr308 in the T-loop and Ser473 in the hydrophobic domain. In contrast, AKT2 was only phosphorylated at the equivalent sites (Thr309 and Ser474) at low levels. Further, Thr308 and Ser473 phosphorylation occurred predominantly on the same AKT1 molecules, whereas Thr309 and Ser474 were phosphorylated primarily on different AKT2 molecules. Although basal AKT2 phosphorylation was sensitive to inhibition of phosphatidylinositol 3-kinase (PI3K), basal AKT1 phosphorylation was essentially resistant. -
MAP Kinase Kinase Kinase, MEKK, MAPKKK
MAP3K MAP kinase kinase kinase, MEKK, MAPKKK MAP3Ks (Mitogen-activated protein kinase kinase kinases), the top components of MAPK cascades, provide specificity for stimulus-dependent activation of MAP2K-MAPK pathways through unique protein-protein interactions and phosphorylation of signaling effectors. The MAP3Ks are highly divergent in gene numbers and structure, including TAK1, ASK1, A-Raf and C-Raf. MAPK system is a three-step sequential phosphorylation cascade which is composed of MAPK, MAP2K, and MAP3K. ERK, p38 MAPK, and JNK, which are known to be activated by mechanical stimuli, belong to the MAPK family. MAP3Ks function as “platforms to integrate MAPK signaling, and activation of multiple MAP3Ks provides the spatiotemporal regulation of the MAPK pathways, which induces a wide range of physiological responses required for determining cell fate, such as cytokine production, survival, differentiation and apoptosis”. www.MedChemExpress.com 1 MAP3K Inhibitors 5Z-7-Oxozeaenol ASK1-IN-2 (FR148083; L783279; LL-Z 1640-2) Cat. No.: HY-12686 Cat. No.: HY-131969 5Z-7-Oxozeaenol is a natural anti-protozoan ASK1-IN-2 is a potent and orally active inhibitor compound from fungal origin, acting as a potent of apoptosis signal-regulating kinase 1 (ASK1), irreversible and selective inhibitor of TAK1 and with an IC50 of 32.8 nM. ASK1-IN-2 can be used for VEGF-R2, with IC50s of 8 nM and 52 nM, the research of ulcerative colitis. respectively. Purity: ≥99.0% Purity: 98.49% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg Cot inhibitor-1 Cot inhibitor-2 Cat.