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A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.

ABSTRACT: 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 1-2 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.

SUBMITTER: Aguilar A

PROVIDER: S-EPMC3806060 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.

Aguilar Angelo A Zhou Haibin H Chen Jianfang J Liu Liu L Bai Longchuan L McEachern Donna D Yang Chao-Yie CY Meagher Jennifer J Stuckey Jeanne J Wang Shaomeng S

Journal of medicinal chemistry 20130322 7

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 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. ...[more]

PMID: 23448298

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