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Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

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journal contribution
posted on 15.03.2016, 00:00 by Alexander M. Taylor, Alexandre Côté, Michael C. Hewitt, Richard Pastor, Yves Leblanc, Christopher G. Nasveschuk, F. Anthony Romero, Terry D. Crawford, Nico Cantone, Hariharan Jayaram, Jeremy Setser, Jeremy Murray, Maureen H. Beresini, Gladys de Leon Boenig, Zhongguo Chen, Andrew R. Conery, Richard T. Cummings, Leslie A. Dakin, E. Megan Flynn, Oscar W. Huang, Susan Kaufman, Patricia J. Keller, James R. Kiefer, Tommy Lai, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Henry Lu, Eneida Pardo, Vickie Tsui, Jian Wang, Yongyun Wang, Zhaowu Xu, Fen Yan, Dong Yu, Laura Zawadzke, Xiaoqin Zhu, Xiaoyu Zhu, Robert J. Sims, Andrea G. Cochran, Steve Bellon, James E. Audia, Steven Magnuson, Brian K. Albrecht
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo­[b]­[1,4]­diazepin-2-one.