Potent and Selective BCL-XL Inhibitors and PROTAC Compounds as Potential Cancer Treatment and Immunotherapy

Abstract

The B-cell lymphoma 2 (BCL-2) protein is the most extensively studied anti-apoptotic member within the BCL-2 protein family. It functions to inhibit programmed cell death by forming a heterodimer with BAX, thereby promoting cellular survival through the extension of tumor cell lifespan and facilitating malignant transformation. This Patent Highlight reveals the development of small molecule degraders that consist of a ligand targeting the protein of interest, BCL-2, an E3 ubiquitin ligase recruitment ligand (such as Cereblon or Von Hippel–Lindau ligands), and a chemical linker that connects the two ligands. The proteolysis-targeting chimera (PROTAC)-mediated heterodimerization of the bound proteins leads to the ubiquitination of the target protein, which is subsequently degraded by the proteasome. This strategy offers innovative therapeutic options for cancer, immunology, and autoimmune disease management.