Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors

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• 作者：Paul Bamborough ; Chun-wa Chung ; Rebecca C. Furze ; Paola Grandi ; Anne-Marie Michon ; Robert J. Sheppard ; Heather Barnett ; Hawa Diallo ; David P. Dixon ; Clement Douault ; Emma J. Jones ; Bhumika Karamshi ; Darren J. Mitchell ; Rab K. Prinjha ; Christina Rau ; Robert J. Watson ; Thilo Werner ; Emmanuel H. Demont
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6151-6178
• 全文大小：1010K
• ISSN：1520-4804

文摘

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 naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.