Co-targeting BCL-XL and BCL-2 by PROTAC 753B Eliminates Leukemia Cells and Enhances Efficacy of Chemotherapy by Targeting Senescent Cells

Authors

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

Publication Date

10-1-2023

Journal

Haematologica

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.

Keywords

Humans, bcl-X Protein, Proto-Oncogene Proteins c-bcl-2, Antineoplastic Agents, Leukemia, Myeloid, Acute, Cellular Senescence, Cell Line, Tumor, Apoptosis

DOI

10.3324/haematol.2022.281915

PMID

37078252

PMCID

PMC10542840

PubMedCentral® Posted Date

April 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes