Structure-Based Design of 纬-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors

详细信息    查看全文

• 作者：Xu Ran ; Yujun Zhao ; Liu Liu ; Longchuan Bai ; Chao-Yie Yang ; Bing Zhou ; Jennifer L. Meagher ; Krishnapriya Chinnaswamy ; Jeanne A. Stuckey ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：4927-4939
• 全文大小：585K
• ISSN：1520-4804

文摘

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of 纬-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with K_i values of 3.2鈥?4.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 脜 resolution, which provides a solid structural basis for the compound鈥檚 high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.