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

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

  • ACS Med Chem Lett. 2016 Mar 15;7(5):531-6. doi: 10.1021/acsmedchemlett.6b00075.
Alexander M Taylor 1,  Alexandre Côté 1,  Michael C Hewitt 1,  Richard Pastor 2,  Yves Leblanc 1,  Christopher G Nasveschuk 1,  F Anthony Romero 2,  Terry D Crawford 2,  Nico Cantone 1,  Hariharan Jayaram 1,  Jeremy Setser 1,  Jeremy Murray 2,  Maureen H Beresini 2,  Gladys de Leon Boenig 2,  Zhongguo Chen 3,  Andrew R Conery 1,  Richard T Cummings 1,  Leslie A Dakin 1,  E Megan Flynn 2,  Oscar W Huang 2,  Susan Kaufman 2,  Patricia J Keller 1,  James R Kiefer 2,  Tommy Lai 3,  Yingjie Li 3,  Jiangpeng Liao 3,  Wenfeng Liu 3,  Henry Lu 3,  Eneida Pardo 1,  Vickie Tsui 2,  Jian Wang 3,  Yongyun Wang 3,  Zhaowu Xu 3,  Fen Yan 3,  Dong Yu 3,  Laura Zawadzke 1,  Xiaoqin Zhu 3,  Xiaoyu Zhu 3,  Robert J Sims 3rd 1,  Andrea G Cochran 2,  Steve Bellon 1,  James E Audia 1,  Steven Magnuson 2,  Brian K Albrecht 1
Affiliations

Affiliations

  • 1 Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
  • 2 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 3 Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
PMID: 27190605 DOI: 10.1021/acsmedchemlett.6b00075
Abstract

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.

Keywords

Bromodomain; CBP; CREBBP; EP300; benzodiazepinone.

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