Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors

被引：72

作者：

Bamborough, Paul ^{[1
]}

Chung, Chun-wa ^{[1
]}

Furze, Rebecca C. ^{[2
]}

Grandi, Paola ^{[4
]}

Michon, Anne-Marie ^{[4
]}

Sheppard, Robert J. ^{[2
]}

Barnett, Heather ^{[3
]}

Diallo, Hawa ^{[2
]}

Dixon, David P. ^{[1
]}

Douault, Clement ^{[2
]}

Jones, Emma J. ^{[1
]}

Karamshi, Bhumika ^{[1
]}

Mitchell, Darren J. ^{[2
]}

Prinjha, Rab K. ^{[2
]}

Rau, Christina ^{[4
]}

Watson, Robert J. ^{[2
]}

Wemer, Thilo ^{[4
]}

Demont, Emmanuel H. ^{[2
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Mol Discovery Res, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline Med Res Ctr, Epinova Discovery Performance Unit, Stevenage SG1 2NY, Herts, England

[3] GlaxoSmithKline Med Res Ctr, Flexible Discovery Unit, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline, Mol Discovery Res, Cellzome GmbH, D-69117 Heidelberg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 15期

关键词：

DISCOVERY;

D O I：

10.1021/acs.jmedchem.5b00773

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphth-yridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

引用

页码：6151 / 6178

页数：28

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