[1,2,4]Triazolo[4,3-a]phthalazines: Inhibitors of Diverse Bromodomains

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• 作者：Oleg Fedorov ; Hannah Lingard ; Chris Wells ; Octovia P. Monteiro ; Sarah Picaud ; Tracy Keates ; Clarence Yapp ; Martin Philpott ; Sarah J. Martin ; Ildiko Felletar ; Brian D. Marsden ; Panagis Filippakopoulos ; Susanne Müller ; Stefan Knapp ; Paul E. Brennan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 23, 2014
• 年：2014
• 卷：57
• 期：2
• 页码：462-476
• 全文大小：808K
• ISSN：1520-4804

文摘

Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.