A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

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• 作者：Angelo Aguilar ; Haibin Zhou ; Jianfang Chen ; Liu Liu ; Longchuan Bai ; Donna McEachern ; Chao-Yie Yang ; Jennifer Meagher ; Jeanne Stuckey ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3048-3067
• 全文大小：730K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K_i values of <1 nM and inhibits cancer cell growth with IC₅₀ values of 1鈥? nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.