Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.

ABSTRACT: Checkpoint kinase-1 (CHK1) controls DNA replication and repair. Tumor cells depend on CHK1, whose high levels are associated with worse patient prognosis. We define a bona fide proteolysis-targeting-chimera (PROTAC) for CHK1. PROTAC MA203 contains the type I kinase inhibitor rabusertib, which preferentially inhibits activated CHK1, and the cereblon (CRBN) ligand pomalidomide. MA203 accelerates CRBN-dependent proteasomal degradation of CHK1 in solid tumor-derived cells and acute leukemia cells. Chemotherapy-induced DNA replication stress and a consequent activation of CHK1 accelerate this event-driven process which promotes DNA damage and tumor cell apoptosis. Biochemical and cellular target engagement studies confirm the potency and selectivity of MA203. MA203 does not damage healthy diffe

SUBMITTER: Ashry R 

PROVIDER: S-EPMC12668314 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature