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J Med Chem. 2013 Apr 11;56(7):3048-3067. doi: 10.1021/jm4001105. Epub 2013 Mar 22.

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

Author information

1
Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
2
Life Sciences Institute, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
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Contributed equally

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
PMCID:
PMC3806060
DOI:
10.1021/jm4001105
[Indexed for MEDLINE]
Free PMC Article

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