Inhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases.
An overview of IAPs
Apoptosis is an active process of death. The activation, expression and regulation of a series of genes are spontaneous and ordered after stimulation of normal cells. Apoptosis and proliferation play an important role in maintaining the normal development and homeostasis of the organism. The inhibitors of apoptosis proteins (IAPs), also known as BIRCs (BIR domain containing proteins), are a class of anti-apoptotic regulators that block cell death and are overexpressed in a variety of human cancer cells. The inhibitors of apoptosis proteins help cells escape apoptosis and promote cell survival.
Major types of IAPs
CROOK et al first discovered IAPs in the baculovirus CpGV and IAPs are a new class of anti-apoptotic proteins independent of the Bcl-2 family. To date, eight known mammalian IAPs have been studied: cellular IAP-1 (c-IAP1), cellular IAP-2 (c-IAP-2), X-chromosome linked IAP (XIAP), neuronal apoptosis inhibitory protein (NAIP), IAP like protein 2 (ILP-2), surviving, bruce and melanoma IAP (MLIAP).
Antagonists of the IAPs
High expression of XIAP, c-IAP1 and c-IAP2 is observed in the developmental stages and poor prognosis of malignant tumors, which allow cancer cells to survive in human body. Therefore, it can promote tumor cell apoptosis by antagonizing IAPs to stimulate the apoptotic signal to become stronger. At present, the most concerned IAP antagonists are mainly divided into two types: Smac mimetics and non-peptide small molecule compounds. Smac is a mitochondrial binding protein promoting cell apoptosis that is highly expressed in normal tissues such as heart, liver, kidney, spleen, prostate, thymus and intestine. The synthesis of Smac mimetics with high efficiency, low toxicity and specific targets can inhibit the functional regions of c-IAPs and ultimately plays a role in the treatment of tumors and hepatitis B virus. Currently, four small molecule IAPs antagonists are used for human clinical trial activity assessment: AT-406 /Debio 1143, GDC-0917/CUDC-427 and LCL161, TL-32711.
IAPs and diseases
With the recognition of apoptosis suppression as a fundamental aspect of human cancer, the IAPs can be used as an outstanding target for cancer diagnosis and treatment, and has attracted much attention in cancer research.
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