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

被引：21

作者：

Lai, Kwong Wah ^{[1
]}

Romero, F. Anthony ^{[2
]}

Tsui, Vickie ^{[2
]}

Beresini, Maureen H. ^{[2
]}

Boenig, Gladys de Leon ^{[2
]}

Bronner, Sarah M. ^{[2
]}

Chen, Kevin ^{[1
]}

Chen, Zhongguo ^{[1
]}

Choo, Edna F. ^{[2
]}

Crawford, Terry D. ^{[2
]}

Cyr, Patrick ^{[2
]}

Kaufman, Susan ^{[2
]}

Li, Yingjie ^{[1
]}

Liao, Jiangpeng ^{[1
]}

Liu, Wenfeng ^{[1
]}

Ly, Justin ^{[2
]}

Murray, Jeremy ^{[2
]}

Shen, Weichao ^{[1
]}

Wai, John ^{[1
]}

Wang, Fei ^{[1
]}

Zhu, Caicai ^{[1
]}

Zhu, Xiaoyu ^{[1
]}

Magnuson, Steven ^{[2
]}

机构：

[1] WuXi AppTec Co Ltd, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

[2] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 01期

关键词：

Bromodomain; CBP inhibitor; Volume of distribution; Half-life; CREB-BINDING-PROTEIN; CBP; COACTIVATOR; ACETYLATION; P300; DOMAIN;

D O I：

10.1016/j.bmcl.2017.11.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：15 / 23

页数：9

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