Novel SMAC Mimetics as Peptide-based Small Molecule Inhibitors of IAPs to Induce Apoptosis in Cancer Cells

Abstract

SMAC (Secondary Mitochondria-derived Activator of Caspases) mimetics have generated significant interest as potential chemotherapeutic compounds via their ability to promote apoptosis in cancer cells. These molecules target several Inhibitor of Apoptosis Proteins (IAPs) whose elevated expression is ubiquitous with tumorigenesis. We report several novel SMAC based peptidomimetics which appear to mirror the anti-IAP activity of SMAC in vitro. Elements of reported SMAC mimetics were combined with unique structural features to design novel, efficacious IAP antagonists. Our approach included modifications to the 2nd and 4th residues of the AVPI peptide sequence, the motif responsible for SMAC 's interaction with IAPs. Cell-based compound testing against MDA-MB-231 breast cancer cells identified several promising leads possessing nanomolar cytotoxic effects. Apoptotic activity was confirmed via capsase-3/7 activation, a hallmark of regulated cell death. Our experimental data suggests we have developed selective, potent anti-cancer compounds to be further developed in the pursuit of new anti-cancer therapeutics.