Structure Enabled Design of BAZ2-ICR, A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B

被引：78

作者：

Drouin, Ludovic ^{[1
]}

McGrath, Sally ^{[1
]}

Vidler, Lewis R. ^{[1
]}

Chaikuad, Apirat ^{[2
]}

Monteiro, Octovia ^{[2
,3
]}

Tallant, Cynthia ^{[2
,3
]}

Philpott, Martin ^{[2
,3
]}

Rogers, Catherine ^{[2
,3
]}

Fedorov, Oleg ^{[2
,3
]}

Liu, Manjuan ^{[1
]}

Akhtar, Wasim ^{[1
]}

Hayes, Angela ^{[1
]}

Raynaud, Florence ^{[1
]}

Mueller, Susanne ^{[2
,3
]}

Knapp, Stefan ^{[2
,3
]}

Hoelder, Swen ^{[1
]}

机构：

[1] Inst Canc Res, Div Canc Therapeut, Canc Res UK Canc Therapeut Unit, London SM2 5NG, England

[2] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ, England

[3] Univ Oxford, Target Discovery Inst, Oxford OX3 7FZ, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 05期

基金：

加拿大创新基金会; 英国惠康基金; 英国工程与自然科学研究理事会;

关键词：

SMALL-MOLECULE INHIBITORS; DISCOVERY; FAMILY; NORC; RECOGNITION; LIGANDS;

D O I：

10.1021/jm501963e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe for functional studies of the BAZ2 bromodomains in vitro and in vivo.

引用

页码：2553 / 2559

页数：7

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