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
  • 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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