Introduction of IAP
Apoptosis, or programmed death, is a natural cell cycle process designed to eliminate unwanted or damaged cells from the body. In healthy tissues, there is a good regulatory balance between pro-apoptotic proteins and anti-apoptotic proteins, and they work together to regulate apoptosis. However, cancer cells inhibit apoptosis by up-regulating the expression of anti-apoptotic proteins, which eventually leads to problems such as tumor growth, poor prognosis and drug resistance.
IAP (Inhibitor of Apoptosis) can inhibit intracellular apoptosis, and its dysregulation is usually associated with inflammation, tumorgenesis and growth. Apoptosis inhibitor proteins (IAPs) were first discovered in baculovirus in 1993. Up to now, eight IAPs protein family members have been discovered successively, including NAIP, C-IAP1, C-IAP2, XIAP, Survivin, Bruce, ILP-2 and Livin.
IAP can directly bind caspase, inhibit caspase activity and prevent apoptosis. Caspases are a class of cysteine proteases that play a synergistic role in the cascade of apoptosis signaling. When subjected to pro-apoptotic stimuli including Fasl, TNF, Granzyme-B, etc., Caspase activation can lead to the release of pro-apoptotic factor CytoC on the one hand, and activate the release of Smac protein on the other hand, antagonizing the binding of IAPs to Caspase protein. The result of this cascade is the lysis of a large number of proteins in the cell, the disintegration and death of the cell, and finally the phagocytosis and the removal of cell debris. However, when the anti-apoptotic protein is overexpressed, it inhibits the activity of caspase by binding with caspase kinase and prevents cell apoptosis.
IAP Inhibitors
IAP inhibitors can be divided into Smac mimics and non-peptide small molecules. Smac mimics can be divided into monomer and dimer inhibitors according to the number of binding sites. Monomer inhibitors can bind to XIAP, cIAP1 and cIAP2 to activate caspase-9 activity and remove the inhibitory effect of IAP on caspase. Related drugs include LCL161, AT-406, etc. Dimer inhibitors, including APG-1387, activate caspase-3/7/9 activity to promote apoptosis.
1. LCL161
LCL161 is a small molecule Smac mimetic that inhibits multiple inhibitor of apoptosis (IAP) family proteins. LCL-161 exhibits synergistic antitumor activity in both in vitro and in vivo models of resistant lymphoma.
2. AT-406
AT-406 is a potent oral IAP antagonist with potent apoptotic protein inhibitors, with IC50 values of 12.3, 22.1 and 225nmol/L for cIAP1, cIAP2 and XIAP proteins, respectively. In February 2020, AT-406 received breakthrough therapy designation from the FDA for the treatment of unresectable locally advanced squamous cell carcinoma of the head and neck in combination with standard chemotherapy and radiotherapy regiments.
3. APG-1387
APG-1387 is a potent, bivalent small-molecule Inhibitor of Apoptosis Protein (IAP) antagonist. It has shown strong dose- and schedule-dependent antitumor activities in multiple human cancer xenograft models, APG-1387 also demonstrates its synergistic effect in combination with immune checkpoint inhibitor anti-PD-1 antibody, and such a combinatory effect was further enhanced by chemotherapeutic agent.
IAP is an important regulator of apoptosis and pro-survival signaling pathways, and its dysregulation is often associated with tumorgenesis and growth. In addition to oncology indications, clinical trials of IAP inhibitors for hepatitis B are also progressing. Globally, although no IAP inhibitors have been approved, they are expected to shine as research progresses.