753B

753B (also known as PZ18753b) is a novel, dual BCL-XL and BCL-2 proteolysis-targeting chimera (PROTAC) developed by Dialectic Therapeutics in collaboration with the University of Florida and MD Anderson Cancer Center. It is designed to recruit the von Hippel-Lindau (VHL) E3 ligase to induce the ubiquitination and subsequent proteasomal degradation of both BCL-XL and BCL-2 anti-apoptotic proteins. Unlike the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263), 753B is engineered to spare platelets from on-target toxicity because platelets lack significant VHL expression. Preclinical studies have demonstrated that 753B effectively reduces cell viability and induces dose-dependent degradation of its targets in various leukemia subsets, including acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Furthermore, 753B exhibits senolytic activity, allowing it to eliminate chemotherapy-induced senescent leukemia cells that contribute to chemoresistance and disease relapse.

Other names

BCL-XL/BCL-2 PROTAC 753B