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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

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Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States
*Tel: +1-609-252-4320. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2015, 6, 8, 850–855
Publication Date (Web):July 12, 2015
https://doi.org/10.1021/acsmedchemlett.5b00226
Copyright © 2015 American Chemical Society

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Abstract

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JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

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Full experimental details for key compounds and biological protocols. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00226.

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  2. Neil A. Strotman, Maxime C. Soumeillant, Keming Zhu, Chester E. Markwalter, Carolyn S. Wei, Yi Hsiao, Martin D. Eastgate. Effects of Multiple Catalyst Deactivation Pathways and Continuous Ligand Recycling on the Kinetics of Pd-Catalyzed C–N Coupling Reactions. The Journal of Organic Chemistry 2019, 84 (8) , 4653-4660. https://doi.org/10.1021/acs.joc.8b02214
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  14. Pengfei Xu, Pei Shen, Bin Yu, Xi Xu, Raoling Ge, Xinying Cheng, Qiuyu Chen, Jinlei Bian, Zhiyu Li, JuBo Wang. Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders. European Journal of Medicinal Chemistry 2020, 192 , 112155. https://doi.org/10.1016/j.ejmech.2020.112155
  15. Fatima Ezzahra Bennani, Latifa Doudach, Yahia Cherrah, Youssef Ramli, Khalid Karrouchi, M'hammed Ansar, My El Abbes Faouzi. Overview of recent developments of pyrazole derivatives as an anticancer agent in different cell line. Bioorganic Chemistry 2020, 97 , 103470. https://doi.org/10.1016/j.bioorg.2019.103470
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  18. Francesca Musumeci, Chiara Greco, Ilaria Giacchello, Anna Lucia Fallacara, Munjed M. Ibrahim, Giancarlo Grossi, Chiara Brullo, Silvia Schenone. An Update on JAK Inhibitors. Current Medicinal Chemistry 2019, 26 (10) , 1806-1832. https://doi.org/10.2174/0929867325666180327093502
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  21. Ning Ding, Sam A. Miller, Sudha S. Savant, Heather M. O'Hagan. JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage. Environmental and Molecular Mutagenesis 2019, 60 (4) , 308-319. https://doi.org/10.1002/em.22269
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  23. Hui Gao, Songqing Mei, Jing Zhao, Kangcheng Zheng, Siyan Liao. Study on the binding mode of a pyrrolotriazin derivative with JAK2 by docking and MD simulation. Molecular Simulation 2019, 45 (3) , 230-238. https://doi.org/10.1080/08927022.2018.1557330
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  29. Ting-Ting Yao, Jiang-Feng Xie, Xing-Guo Liu, Jing-Li Cheng, Cheng-Yuan Zhu, Jin-Hao Zhao, Xiao-Wu Dong. Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors. RSC Advances 2017, 7 (17) , 10353-10360. https://doi.org/10.1039/C6RA24959K
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  31. Siyu Wang, Rong Jin, Ruiquan Wang, Yongzhou Hu, Xiaowu Dong, Ai e Xu. The design, synthesis and biological evaluation of pro-EGCG derivatives as novel anti-vitiligo agents. RSC Advances 2016, 6 (108) , 106308-106315. https://doi.org/10.1039/C6RA23172A

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