Inhibitor of apoptosis protein family (cIAP1, cIAP2, XIAP, ML-IAP) (IAP family)

The Inhibitor of Apoptosis Protein (IAP) family, specifically cIAP1 (BIRC2), cIAP2 (BIRC3), XIAP (BIRC4), and ML-IAP (BIRC7), represents a group of proteins that play a critical role in regulating programmed cell death and inflammatory signaling (UniProt Q13490, P98170). These proteins are characterized by Baculoviral IAP Repeat (BIR) domains, which facilitate interactions with various signaling proteins, including caspases and the endogenous antagonist Smac/DIABLO (PMID: 22437613). XIAP is a potent direct inhibitor of caspases-3, -7, and -9, while cIAP1 and cIAP2 primarily function as E3 ubiquitin ligases that modulate NF-kappaB signaling to promote cell survival (PMID: 28438777). In many malignancies, IAPs are overexpressed, leading to apoptosis resistance and poor prognosis, making them attractive therapeutic targets. Drugs known as Smac mimetics or IAP antagonists, such as Xevinapant and Birinapant, bind to the BIR domains of these proteins. This binding triggers the rapid autoubiquitination and proteasomal degradation of cIAP1 and cIAP2 and prevents XIAP from inhibiting caspases, thereby sensitizing tumor cells to apoptosis induced by TNF-alpha or other pro-apoptotic stimuli (PMID: 24469416).

Other names

Baculoviral IAP repeat-containing proteinBIRC familyCellular inhibitor of apoptosis protein 1 (cIAP1)Cellular inhibitor of apoptosis protein 2 (cIAP2)X-linked inhibitor of apoptosis protein (XIAP)Melanoma inhibitor of apoptosis protein (ML-IAP)LivinBIRC2BIRC3BIRC4BIRC7

IAP antagonists, also known as Smac mimetics, bind to the Baculoviral IAP Repeat (BIR) domains of IAP proteins. This binding induces the rapid autoubiquitination and proteasomal degradation of cIAP1 and cIAP2, while also blocking the ability of XIAP to inhibit caspases-3, -7, and -9, thereby lowering the threshold for apoptosis (PMID: 22437613, PMID: 28438777).