Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells

Yannan Jia, Lina Han, Cassandra L. Ramage, Zhe Wang, Connie C. Weng, Lei Yang, Simona Colla, Helen Ma, Weiguo Zhang, Michael Andreeff, Naval Daver, Nitin Jain, Naveen Pemmaraju, Kapil Bhalla, Satu Mustjoki, Peiyi Zhang, Guangrong Zheng, Daohong Zhou, Qi Zhang, Marina Konopleva

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the Von Hippel-Lindau (VHL) E3 ligase, leading to BCL-XL/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-XL/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-XL and BCL-2 in a subset of hematopoietic cell lines, AML primary samples and in vivo PDX AML model. We further demonstrated the senolytic activity of 753B which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.