Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression

详细信息    查看全文

• 作者：Jianfang Chen ; Haibin Zhou ; Angelo Aguilar ; Liu Liu ; Longchuan Bai ; Donna McEachern ; Chao-Yie Yang ; Jennifer L. Meagher ; Jeanne A. Stuckey ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8502-8514
• 全文大小：596K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K_i < 1 nM and has low nanomolar IC₅₀ values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.