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J Med Chem. 2012 Jan 12;55(1):106-14. doi: 10.1021/jm201072x. Epub 2011 Dec 7.

Bivalent Smac mimetics with a diazabicyclic core as highly potent antagonists of XIAP and cIAP1/2 and novel anticancer agents.

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


Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3-10 nM. The most potent compounds in the series have IC(50) of 3-5 nM in inhibition of cell growth in both MDA-MB-231 and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.

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