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
Affiliations
Yannan Jia
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
Lina Han
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Cassandra L. Ramage
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Zhe Wang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Connie C. Weng
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Lei Yang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Simona Colla
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Helen Ma
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Weiguo Zhang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Michael Andreeff
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Naval Daver
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Nitin Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Naveen Pemmaraju
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Kapil Bhalla
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Satu Mustjoki
Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer center, Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki
Peiyi Zhang
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL
Guangrong Zheng
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL
Daohong Zhou
Department of Biochemistry and Structural Biology and Center for Innovative Drug Discovery, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
Qi Zhang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Marina Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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.
