Structure-Based Design of Potent Bcl-2/Bcl-xL Inhibitors with Strong in Vivo Antitumor Activity

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• 作者：Haibin Zhou ; Angelo Aguilar ; Jianfang Chen ; Longchuan Bai ; Liu Liu ; Jennifer L. Meagher ; Chao-Yie Yang ; Donna McEachern ; Xin Cong ; Jeanne A. Stuckey ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：55
• 期：13
• 页码：6149-6161
• 全文大小：664K
• 年卷期：v.55,no.13(July 12, 2012)
• ISSN：1520-4804

文摘

Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 脜 resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K_i values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC₅₀ values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.