TY - JOUR AU - Jia, Yannan AU - Han, Lina AU - Ramage, Cassandra L. AU - Wang, Zhe AU - Weng, Connie C. AU - Yang, Lei AU - Colla, Simona AU - Ma, Helen AU - Zhang, Weiguo AU - Andreeff, Michael AU - Daver, Naval AU - Jain, Nitin AU - Pemmaraju, Naveen AU - Bhalla, Kapil AU - Mustjoki, Satu AU - Zhang, Peiyi AU - Zheng, Guangrong AU - Zhou, Daohong AU - Zhang, Qi AU - Konopleva, Marina PY - 2023/10/01 Y2 - 2024/03/29 TI - Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells JF - Haematologica JA - haematol VL - 108 IS - 10 SE - Articles DO - 10.3324/haematol.2022.281915 UR - https://haematologica.org/article/view/haematol.2022.281915 SP - 2626-2638 AB - 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 BCLX 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-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, 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 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. ER -