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BCL-X L and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-X L/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-X L and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCL-X L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-X L/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-X L and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of …