TY  - JOUR
AU  - Ashry, Ramy
AU  - Abdelsalam, Mohamed
AU  - Hausen, Julia
AU  - Hieber, Christoph
AU  - Zeyn, Yanira
AU  - Sarnow, Anne-Christin
AU  - Schmidt, Matthias
AU  - Najafi, Sara
AU  - Oehme, Ina
AU  - Bros, Matthias
AU  - Chen, Jia-Xuan
AU  - Dejung, Mario
AU  - Sippl, Wolfgang
AU  - Krämer, Oliver H
TI  - Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.
JO  - Angewandte Chemie / International edition
VL  - nn
SN  - 1433-7851
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2025-02159
SP  - nn
PY  - 2025
N1  - epub
AB  - 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 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-suppressive 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-known catalytic activity. Thus, kinase-independent functions of CHK1 can be exploited with innovative pharmacological agents.
KW  - CHK1 (Other)
KW  - Cancer cells (Other)
KW  - Cereblon (Other)
KW  - DNA replication stress (Other)
KW  - PROTAC (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41104666
DO  - DOI:10.1002/anie.202514788
UR  - https://inrepo02.dkfz.de/record/305441
ER  -