title: 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 concentrations in cancer cells with a mechanism of action similar to that of other known Smac mimetics. Our study shows that binding of Smac mimetics to XIAP BIR3 is not required for effective induction of apoptosis in tumor cells by Smac mimetics. These potent and highly selective cIAP1/2 inhibitors are powerful tools in the investigation of the role of these IAP proteins in the regulation of apoptosis and other cellular processes.
authors: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, United States.
authors: Haiying
authors: H
authors: Sun
authors: Jianfeng
authors: J
authors: Lu
authors: Liu
authors: L
authors: Liu
authors: Chao-Yie
authors: CY
authors: Yang
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001681:Biological Assay; D032701:Biomimetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003198:Computer Simulation; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide; D054852:Small Molecule Libraries; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases