2. Academic Validation
  3. Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300

Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300

  • Bioorg Med Chem Lett. 2018 Jan 1;28(1):15-23. doi: 10.1016/j.bmcl.2017.11.025.
Kwong Wah Lai 1,  F Anthony Romero 2,  Vickie Tsui 3,  Maureen H Beresini 2,  Gladys de Leon Boenig 2,  Sarah M Bronner 2,  Kevin Chen 1,  Zhongguo Chen 1,  Edna F Choo 2,  Terry D Crawford 2,  Patrick Cyr 2,  Susan Kaufman 2,  Yingjie Li 1,  Jiangpeng Liao 1,  Wenfeng Liu 1,  Justin Ly 2,  Jeremy Murray 2,  Weichao Shen 1,  John Wai 1,  Fei Wang 1,  Caicai Zhu 1,  Xiaoyu Zhu 1,  Steven Magnuson 4
Affiliations

Affiliations

  • 1 WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
  • 2 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 4 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 29169673 DOI: 10.1016/j.bmcl.2017.11.025
Abstract

A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.

Keywords

Bromodomain; CBP inhibitor; Half-life; Volume of distribution.

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