Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy

Dear Colleagues,

The major hallmarks of cancer development involve a cascade of events including loss of control for cell death, induced by the interruption of extrinsic and intrinsic apoptotic pathways, such as TP53, caspases, TNF, TNF-related apoptosis-inducing ligand (TRAIL), and inhibitor of apoptosis proteins (IAPs). Recently, The Cancer Genome Atlas (TCGA) revealed genomic and expression alterations of various components in the death pathway in many malignancies, such as TP53 and caspase mutations, the deletion of TRAIL receptors, and amplification and overexpression of the Fas-associated via death domain (FADD) and IAPs. These molecules and complexes are critical in cell death, survival, and drug resistance. The IAP molecules are defined by the presence of Baculoviral IAP Repeat (BIR) domains, which mediate protein–protein interactions. The major IAP family proteins in mammalian include c-IAP1, c-IAP2, and XIAP, which function as endogenous inhibitors of caspases involved in both intrinsic and extrinsic pathways. A strong endogenous antagonist of IAP proteins has been identified in the intrinsic death pathway, which is a mitochondrial protein known as a second mitochondria-derived activator of caspases (SMAC). When SMAC is released from the mitochondria, it binds to IAPs, relieves the inhibition of caspases, and leads to the apoptotic cascade. SMAC mimetic or synthetic IAP antagonist therapy has been developed as the major strategy to inhibit IAPs and induce cell death in cancer preclinical models and patients. The optimal activity of SMAC mimetics therapy has been observed in the combination with the death signals, such as TNF, TRAIL, and FasL. In addition, there are non-SMAC mimetic IAP antagonists used as the therapeutic agents in clinical trials. Most drugs targeting IAPs are still in early phase clinical trials. 

This Special Issue will cover the results of original studies and review articles using preclinical animal or cell culture models to investigate the mechanisms of IAP inhibitors on cancers; the bioinformatics and protein structure analysis of the interaction of IAP proteins and other death molecules; the drug target effects related to the cancer genomic or expression alterations of the molecules involved in the extrinsic and intrinsic death pathways; the network cross-talk among TP53, IAPs, TNF, TRAIL, and other death pathways; regulation of innate and adaptive antitumor immunity by IAP inhibitors; the genomic and molecular biomarkers predicting the efficacy of IAP inhibitors in clinical trials; a combination of IAP inhibitors and conventional chemo- and radiation therapies; as well as the current status and development of new small or large molecules targeting IAP and related death pathways. 

Prof. Zhong Chen
Guest Editor

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• inhibitor of apoptosis proteins (IAPs)
• IAP antagonist
• SMAC mimetic
• extrinsic and intrinsic death pathways
• cancer
• biomarkers
• pre-clinical studies
• clinical trials