Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains
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- 作者：Olivier Mirguet ; Romain Gosmini ; J茅r么me Toum ; Catherine A. Cl茅ment ; M茅lanie Barnathan ; Jean-Marie Brusq ; Jacqueline E. Mordaunt ; Richard M. Grimes ; Miriam Crowe ; Olivier Pineau ; Myriam Ajakane ; Alain Daugan ; Phillip Jeffrey ; Leanne Cutler ; Andrea C. Haynes ; Nicholas N. Smithers ; Chun-wa Chung ; Paul Bamborough ; Iain J. Uings ; Antonia Lewis ; Jason Witherington ; Nigel Parr ; Rab K. Prinjha ; Edwige Nicod猫me
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：October 10, 2013
- 年：2013
- 卷：56
- 期：19
- 页码：7501-7515
- 全文大小：619K
- 年卷期：v.56,no.19(October 10, 2013)
- ISSN：1520-4804
文摘
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure鈥揳ctivity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.