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.
