Targeting the Inhibitor of Apoptosis Proteins with Small Molecules: Recent Advances and Clinical Challenges

Apoptosis is a tightly regulated cellular mechanism that is frequently dysregulated in many human malignancies. Inhibitor of apoptosis (IAP) proteins are preferentially expressed in many cancers and are attractive therapeutic targets. One of the most promising strategies to block IAPs is with small-molecule IAP antagonists. In the past decade, intense research efforts have been dedicated to the development of this novel class of drugs. While currently there are no FDA approved IAP inhibitors, a number of small-molecule inhibitors have moved into clinical trials either as single agents or in combination with existing anticancer drugs. Both monovalent and bivalent IAP inhibitors have been reported. These small-molecule inhibitors have the potential to bring exciting new treatment options to overcome apoptotic resistance for anticancer therapy. However, due to the dynamic nature of IAPs and their involvement in cell signaling, there are still challenges that need to be addressed to optimize their efficacy and incorporate them into eventual clinical regimens. This chapter reviews the biological mechanisms of IAPs as well as provides an update of the recent advances, clinical challenges and potential opportunities for small-molecule IAP inhibitors, particularly SMAC mimetics and survivin antagonists, in anticancer therapeutics.

Keywords: Apoptosis, Cancer therapy, cIAP, IAP antagonists, Inhibitor of apoptosis (IAP) proteins, SMAC, SMAC mimetics, Small-molecule inhibitors, Survivin, XIAP.