Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains

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• 作者：Mathew P. Martin ; Sanne H. Olesen ; Gunda I. Georg ; Ernst Sch枚nbrunn
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：November 15, 2013
• 年：2013
• 卷：8
• 期：11
• 页码：2360-2365
• 全文大小：426K
• 年卷期：v.8,no.11(November 15, 2013)
• ISSN：1554-8937

文摘

Bromodomain-containing proteins are considered atypical kinases, but their potential to interact with kinase inhibitors is unknown. Dinaciclib is a potent inhibitor of cyclin-dependent kinases (CDKs), which recently advanced to Phase III clinical trials for the treatment of leukemia. We determined the crystal structure of dinaciclib in complex with CDK2 at 1.7 脜 resolution, revealing an elaborate network of binding interactions in the ATP site, which explains the extraordinary potency and selectivity of this inhibitor. Remarkably, dinaciclib also interacted with the acetyl-lysine recognition site of the bromodomain testis-specific protein BRDT, a member of the BET family of bromodomains. The binding mode of dinaciclib to BRDT at 2.0 脜 resolution suggests that general kinase inhibitors (鈥渉inge binders鈥? possess a previously unrecognized potential to act as protein鈥損rotein inhibitors of bromodomains. The findings may provide a new structural framework for the design of next-generation bromodomain inhibitors using the vast chemical space of kinase inhibitors.