The Development of Small-Molecule IAP Antagonists for the Treatment of Cancer

Apoptosis is a genetically regulated process of cell death that is critical for cellular homeostasis. Dysregulation of apoptosis can lead to the absence of normal cell death and contribute to cancer development and progression. The Inhibitor of Apoptosis (IAP) proteins contain up to three baculovirus IAP repeat (BIR) domains that interact with members of the caspase family of proteases, thereby blocking apoptosis. Select BIR domains of IAP proteins contain a defined protein-protein interaction region with the N-terminal amino acid residues of the natural IAP antagonist protein, SMAC. Antagonizing this interaction formed the basis of all drug discovery efforts and has yielded promising drug candidates. One member of the IAP family, XIAP, can inhibit caspases 3 and 7 through its BIR2 domain and caspase-9 with its BIR3 domain. The c-IAPs play a key role in the regulation of the NF-κB pathways, which is manipulated by the IAP antagonists to yield single agent activity. SMAC mimicking IAP antagonists can be monovalent, representing an equivalent of four amino acid residues from the processed SMAC, or bivalent – having two units connected through a chemical linker. In addition, antagonists specific for a particular IAP protein or a group of IAPs have been reported. So far, six molecules have entered clinical trials with early results showing no dose limiting toxicities and suggesting that IAP proteins can be targeted by small molecules.