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J Med Chem. 2013 Apr 11;56(7):3048-67. doi: 10.1021/jm4001105. Epub 2013 Mar 22.

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

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  • 1Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109-0934, United States.

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.

PMID:
23448298
[PubMed - indexed for MEDLINE]
PMCID:
PMC3806060
Free PMC Article
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