IAP Proteins and Their Therapeutic Potential

Abstract

Precise regulation of cell death and survival is essential for proper maintenance of organismal homeostasis, development, and immune system. Deregulated cell death can lead to developmental defects, neuropathies, infections, and cancer. Inhibitor of apoptosis (IAP) proteins are evolutionarily conserved regulators of cell death with impact on numerous cellular processes. Initially identified as inhibitors of cell death during viral infection, IAP proteins block cell death by direct inhibition of apoptotic proteases (X chromosome-linked IAP) or by preventing caspase activation following death receptor engagement (cellular IAPs). Recently, the role of IAP proteins as ubiquitin ligases has emerged as a critical feature for their ability to modulate various signaling pathways (e.g., NF-κB, MAPK, NOD) and to influence cellular fate. In addition, IAP proteins are often overexpressed in human malignancies presenting them as attractive targets for anticancer therapy. Among the different strategies employed to target IAP proteins, IAP antagonists—small-molecule mimetics of the natural IAP antagonist SMAC—have garnered most attention. IAP antagonists have successfully passed initial safety scrutiny in clinical trials and are about to enter a critical phase in their development in which their antitumor efficacy will be tested in the hopes of providing novel treatments for cancer patients.