Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold

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• 作者：Haibin Zhou ; Jianfang Chen ; Jennifer L. Meagher ; Chao-Yie Yang ; Angelo Aguilar ; Liu Liu ; Longchuan Bai ; Xin Cong ; Qian Cai ; Xueliang Fang ; Jeanne A. Stuckey ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4664-4682
• 全文大小：854K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 渭M for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott鈥檚 ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K_i < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC₅₀ values of 60鈥?0 nM, and induces robust cell death in the H146 cancer cell line at 30鈥?00 nM.