Potent and selective small-molecule inhibitors of cIAP1/2 proteins reveal that the binding of Smac mimetics to XIAP BIR3 is not required for their effective induction of cell death in tumor cells.

ABSTRACT: Cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked inhibitor of apoptosis protein (XIAP) are key apoptosis regulators and promising new cancer therapeutic targets. This study describes a set of non-peptide, small-molecule Smac (second mitochondria-derived activator of caspases) mimetics that are selective inhibitors of cIAP1/2 over XIAP. The most potent and most selective compounds bind to cIAP1/2 with affinities in the low nanomolar range and show >1,000-fold selectivity for cIAP1 over XIAP. These selective cIAP inhibitors effectively induce degradation of the cIAP1 protein in cancer cells at low nanomolar concentrations and do not antagonize XIAP in a cell-free functional assay. They potently inhibit cell growth and effectively induce apoptosis at low nanomolar concen

SUBMITTER: Sun H 

PROVIDER: S-EPMC4324444 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature