Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor

被引：156

作者：

Martin, Laetitia J. ^{[1
]}

Koegl, Manfred ^{[1
]}

Bader, Gerd ^{[1
]}

Cockcroft, Xiao-Ling ^{[1
]}

Fedorov, Oleg ^{[3
]}

Fiegen, Dennis ^{[2
]}

Gerstberger, Thomas ^{[1
]}

Hofmann, Marco H. ^{[1
]}

Hohmann, Anja F. ^{[4
]}

Kessler, Dirk ^{[1
]}

Knapp, Stefan ^{[3
]}

Knesl, Petr ^{[1
]}

Kornigg, Stefan ^{[1
]}

Muller, Susanne ^{[3
]}

Nar, Herbert ^{[2
]}

Rogers, Catherine ^{[3
]}

Rumpel, Klaus ^{[1
]}

Schaaf, Otmar ^{[1
]}

Steurer, Steffen ^{[1
]}

Tallan, Cynthia ^{[3
]}

Vakoc, Christopher R. ^{[4
]}

Zeeb, Markus ^{[2
]}

Zoephel, Andreas ^{[1
]}

Pearson, Mark ^{[1
]}

Boehmelt, Guido ^{[1
]}

McConnell, Darryl ^{[1
]}

机构：

[1] Boehringer Ingelheim RCV GmbH & Co KG, A-1121 Vienna, Austria

[2] Boehringer Ingelheim Pharma GmbH & Co KG, D-88400 Biberach, Germany

[3] Univ Oxford, SGC, Oxford OX3 7DQ, England

[4] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 10期

基金：

加拿大创新基金会; 美国国家卫生研究院; 英国惠康基金;

关键词：

BROMODOMAIN INHIBITORS; PROGRESS; RECOGNITION; TARGET;

D O I：

10.1021/acs.jmedchem.5b01865

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated in tumors, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold. Crystallographic information on the inhibitors bound to BRD9 guided their development with respect to potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display antitumor activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.

引用

页码：4462 / 4475

页数：14

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