Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

被引：7

作者：

Bennett, Michael J. ^{[1
]}

Wu, Yiqin ^{[1
]}

Boloor, Amogh ^{[1
]}

Matuszkiewicz, Jennifer ^{[1
]}

O'Connell, Shawn M. ^{[1
]}

Shi, Lihong ^{[1
]}

Stansfield, Ryan K. ^{[1
]}

Del Rosario, Joselyn R. ^{[1
]}

Veal, James M. ^{[1
]}

Hosfield, David J. ^{[2
]}

Xu, Jiangchun ^{[1
]}

Kaldor, Stephen W. ^{[1
]}

Stafford, Jeffrey A. ^{[1
]}

Betancort, Juan M. ^{[1
]}

机构：

[1] Celgene Quanticel Res, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA

[2] Univ Chicago, Ben May Dept Canc Res, 929 East 57th St, Chicago, IL 60637 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 10期

关键词：

Epigenetics; Bromodomain inhibitors; BET; BRD4; Fragment; Isoquinolinone; SMALL-MOLECULE INHIBITORS; DISCOVERY; CANCER; PHARMACOLOGY; PROTEINS; PROGRESS; READERS; BRD4;

D O I：

10.1016/j.bmcl.2018.04.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2methylisoquinoline-l-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in <10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies. (C) 2018 E(C) 2vier Ltd. All rights reserved.

引用

页码：1811 / 1816

页数：6

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