Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors

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• 作者：Stuart W. J. Ember ; Jin-Yi Zhu ; Sanne H. Olesen ; Mathew P. Martin ; Andreas Becker ; Norbert Berndt ; Gunda I. Georg ; Ernst Sch枚nbrunn
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：May 16, 2014
• 年：2014
• 卷：9
• 期：5
• 页码：1160-1171
• 全文大小：663K
• 年卷期：v.9,no.5(May 16, 2014)
• ISSN：1554-8937

文摘

Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC₅₀ = 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.