Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity.
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ABSTRACT: Anti-apoptotic protein BCL-XL plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-XL inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-XL to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-XL, we designed and synthesized PROTAC BCL-XL degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-XL/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-XL specific de
SUBMITTER: Zhang X
PROVIDER: S-EPMC7433031 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
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