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

Kwong Wah Lai; F Anthony Romero; Vickie Tsui; Maureen H Beresini; Gladys de Leon Boenig; Sarah M Bronner; Kevin Chen; Zhongguo Chen; Edna F Choo; Terry D Crawford; Patrick Cyr; Susan Kaufman; Yingjie Li; Jiangpeng Liao; Wenfeng Liu; Justin Ly; Jeremy Murray; Weichao Shen; John Wai; Fei Wang; Caicai Zhu; Xiaoyu Zhu; Steven Magnuson

doi:10.1016/j.bmcl.2017.11.025

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. Epub 2017 Nov 14.

Authors

Kwong Wah Lai¹, F Anthony Romero², Vickie Tsui³, Maureen H Beresini², Gladys de Leon Boenig², Sarah M Bronner², Kevin Chen¹, Zhongguo Chen¹, Edna F Choo², Terry D Crawford², Patrick Cyr², Susan Kaufman², Yingjie Li¹, Jiangpeng Liao¹, Wenfeng Liu¹, Justin Ly², Jeremy Murray², Weichao Shen¹, John Wai¹, Fei Wang¹, Caicai Zhu¹, Xiaoyu Zhu¹, Steven Magnuson⁴

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.

MeSH terms

Animals
Binding Sites
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry*
Biphenyl Compounds / metabolism
Cell Cycle Proteins
Crystallography, X-Ray
Drug Design*
Half-Life
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Mice
Microsomes, Liver / metabolism
Molecular Dynamics Simulation
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / metabolism
Protein Structure, Tertiary
Rats
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism
p300-CBP Transcription Factors / antagonists & inhibitors*
p300-CBP Transcription Factors / metabolism

Substances

BRD4 protein, human
Biphenyl Compounds
Cell Cycle Proteins
Nuclear Proteins
Transcription Factors
diphenyl
p300-CBP Transcription Factors