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000305441 1001_ $$00000-0001-6474-113X$$aAshry, Ramy$$b0
000305441 245__ $$aIdentification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.
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000305441 520__ $$aCheckpoint kinase-1 (CHK1) controls DNA replication and repair. Tumor cells depend on CHK1, whose high levels are associated with worse patient prognosis. We define a bona fide proteolysis-targeting-chimera (PROTAC) for CHK1. PROTAC MA203 contains the type I kinase inhibitor rabusertib, which preferentially inhibits activated CHK1, and the cereblon (CRBN) ligand pomalidomide. MA203 accelerates CRBN-dependent proteasomal degradation of CHK1 in solid tumor-derived cells and acute leukemia cells. Chemotherapy-induced DNA replication stress and a consequent activation of CHK1 accelerate this event-driven process which promotes DNA damage and tumor cell apoptosis. Biochemical and cellular target engagement studies confirm the potency and selectivity of MA203. MA203 does not damage healthy differentiated and primitive hematopoietic cells, stromal cells, and retinal epithelial cells. MA203 is superior to its corresponding kinase inhibitor concerning DNA damage, dysregulation of BCL2 proteins, and apoptosis induction. These processes occur independently of the tumor-suppressive transcription factor p53. Elimination of CHK1 protein as structural element, but not its inhibition per se, triggers a proteasomal degradation of key DNA replication and repair proteins. Genetic CHK1 elimination confirms that such newly recognized functions of CHK1 rely on functions beyond its well-known catalytic activity. Thus, kinase-independent functions of CHK1 can be exploited with innovative pharmacological agents.
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000305441 650_7 $$2Other$$aCHK1
000305441 650_7 $$2Other$$aCancer cells
000305441 650_7 $$2Other$$aCereblon
000305441 650_7 $$2Other$$aDNA replication stress
000305441 650_7 $$2Other$$aPROTAC
000305441 7001_ $$00000-0001-6559-2527$$aAbdelsalam, Mohamed$$b1
000305441 7001_ $$aHausen, Julia$$b2
000305441 7001_ $$00009-0002-3343-4203$$aHieber, Christoph$$b3
000305441 7001_ $$00000-0002-2501-8149$$aZeyn, Yanira$$b4
000305441 7001_ $$00009-0008-9261-9316$$aSarnow, Anne-Christin$$b5
000305441 7001_ $$00000-0003-3876-2695$$aSchmidt, Matthias$$b6
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000305441 7001_ $$00000-0002-4662-0542$$aBros, Matthias$$b9
000305441 7001_ $$00000-0002-3671-553X$$aChen, Jia-Xuan$$b10
000305441 7001_ $$00000-0002-0509-0207$$aDejung, Mario$$b11
000305441 7001_ $$00000-0002-5985-9261$$aSippl, Wolfgang$$b12
000305441 7001_ $$00000-0003-3973-045X$$aKrämer, Oliver H$$b13
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