Author:
Jia Yannan,Han Lina,Ramage Cassandra L.,Wang Zhe,Weng Connie C.,Yang Lei,Colla Simona,Ma Helen,Zhang Weiguo,Andreeff Michael,Daver Naval,Jain Nitin,Pemmaraju Naveen,Bhalla Kapil,Mustjoki Satu,Zhang Peiyi,Zheng Guangrong,Zhou Daohong,Zhang Qi,Konopleva Marina
Abstract
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.
Publisher
Ferrata Storti Foundation (Haematologica)
Cited by
3 articles.
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