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Tumor cells depend on CHK1, whose high levels are associated with worse patient prognosis. We define a bona fide proteolysis\u2010targeting\u2010chimera (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\u2010dependent proteasomal degradation of CHK1 in solid tumor\u2010derived cells and acute leukemia cells. Chemotherapy\u2010induced DNA replication stress and a consequent activation of CHK1 accelerate this event\u2010driven 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 differentiated and primitive hematopoietic cells, stromal cells, and retinal epithelial cells. MA203 is superior to its corresponding kinase inhibitor concerning DNA damage, dysregulation of BCL2 proteins, and apoptosis induction. These processes occur independently of the tumor\u2010suppressive transcription factor p53. Elimination of CHK1 protein as structural element, but not its inhibition per se, triggers a proteasomal degradation of key DNA replication and repair proteins. Genetic CHK1 elimination confirms that such newly recognized functions of CHK1 rely on functions beyond its well\u2010known catalytic activity. Thus, kinase\u2010independent functions of CHK1 can be exploited with innovative pharmacological agents.<\/jats:p>","DOI":"10.1002\/anie.202514788","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:01:52Z","timestamp":1760698912000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of a Proteolysis\u2010Targeting\u2010Chimera that Addresses Activated Checkpoint Kinase\u20101 Reveals its Non\u2010Catalytic Functions in Tumor Cells"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6474-113X","authenticated-orcid":false,"given":"Ramy","family":"Ashry","sequence":"first","affiliation":[{"name":"Department of Toxicology University Medical Center  55131 Mainz Germany"},{"name":"Department of Oral Pathology Faculty of Dentistry Mansoura University  Mansoura 35516 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