Anti-apoptotic Proteolysis Targeted Chimeras (PROTACs) in Cancer Therapy

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Targeted protein degradation is an emerging approach for novel drug discovery and basic research. Several degrader molecules have been developed including PROteolysis-TArgeting Chimeras (PROTACs), specific and nongenetic Inhibitor of APoptosis protein (IAP)-dependent Protein ERasers (SNIPERs), IAP antagonists, deubiquitylase inhibitors, hydrophobic tagging molecules, and E3 modulators. The chimeric degrader molecules PROTACs and SNIPERs are made of linking a target protein-ligand to an E3 ubiquitin ligase binding ligand. This modular nature of these chimeric molecules supports versatile protein targets by substituting target ligands. They induce ubiquitylation and proteasomal degradation of the target protein in the cytosol via recruiting an E3 ubiquitin ligase to the target protein. The bridging of the target protein and the E3 ubiquitin ligase facilitates ubiquitylation of the protein and its proteasomal degradation. PROTACs chimeric molecules recruit von Hippel–Lindau or cereblon ubiquitin ligases, while SNIPERs induce simultaneous degradation of cIAP1/2 or XIAP together with the target proteins. Several B-cell Lymphoma 2 (BCL-2) family anti-apoptosis proteins BCL-2, BCL-XL, and MCL-1 are validated anticancer targets and are upregulated in various malignancies. Also, aberrant expression of cIAP1/2 and XIAP with a concomitant increase in apoptosis resistance has been reported. The dysregulation of BCL2 and IAP gene expression in cancer disease is mainly caused by upregulation of the bromodomain and extra-terminal domain (BET) proteins. Degradation of the cellular anti-apoptosis proteins mentioned is a promising approach to induce apoptosis in tumor cells and overcome treatment resistance. Various types of protein degradation strategies have been developed and used. This article overviewed various chimeric compounds capable of inducing the degradation of anti-apoptosis proteins BCL2, BET, and IAP in cancer treatment.