Bivalent Smac Mimetics with a Diazabicyclic Core as Highly Potent Antagonists of XIAP and cIAP1/2 and Novel Anticancer Agents

Abstract

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.