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J Med Chem. 2013 May 23;56(10):3969-79. doi: 10.1021/jm400216d. Epub 2013 May 7.

A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice.

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1
Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

We have designed, synthesized, and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1, and cIAP2 with Ki values of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.

PMID:
23651223
PMCID:
PMC3806058
DOI:
10.1021/jm400216d
[Indexed for MEDLINE]
Free PMC Article

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