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

001     305441
005     20251022115523.0
024 7 _ |a 10.1002/anie.202514788
|2 doi
024 7 _ |a pmid:41104666
|2 pmid
024 7 _ |a 1433-7851
|2 ISSN
024 7 _ |a 0570-0833
|2 ISSN
024 7 _ |a 1521-3773
|2 ISSN
037 _ _ |a DKFZ-2025-02159
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Ashry, Ramy
|0 0000-0001-6474-113X
|b 0
245 _ _ |a Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.
260 _ _ |a Weinheim
|c 2025
|b Wiley-VCH
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1761039913_1629894
|2 PUB:(DE-HGF)
336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
|2 ORCID
336 7 _ |a Journal Article
|0 0
|2 EndNote
500 _ _ |a epub
520 _ _ |a 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.
536 _ _ |a 312 - Funktionelle und strukturelle Genomforschung (POF4-312)
|0 G:(DE-HGF)POF4-312
|c POF4-312
|f POF IV
|x 0
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a CHK1
|2 Other
650 _ 7 |a Cancer cells
|2 Other
650 _ 7 |a Cereblon
|2 Other
650 _ 7 |a DNA replication stress
|2 Other
650 _ 7 |a PROTAC
|2 Other
700 1 _ |a Abdelsalam, Mohamed
|0 0000-0001-6559-2527
|b 1
700 1 _ |a Hausen, Julia
|b 2
700 1 _ |a Hieber, Christoph
|0 0009-0002-3343-4203
|b 3
700 1 _ |a Zeyn, Yanira
|0 0000-0002-2501-8149
|b 4
700 1 _ |a Sarnow, Anne-Christin
|0 0009-0008-9261-9316
|b 5
700 1 _ |a Schmidt, Matthias
|0 0000-0003-3876-2695
|b 6
700 1 _ |a Najafi, Sara
|0 P:(DE-He78)f08873535c440e3ce033c84d5786f70f
|b 7
|u dkfz
700 1 _ |a Oehme, Ina
|0 P:(DE-He78)908367a659dea9e28dac34592b3c46e5
|b 8
|u dkfz
700 1 _ |a Bros, Matthias
|0 0000-0002-4662-0542
|b 9
700 1 _ |a Chen, Jia-Xuan
|0 0000-0002-3671-553X
|b 10
700 1 _ |a Dejung, Mario
|0 0000-0002-0509-0207
|b 11
700 1 _ |a Sippl, Wolfgang
|0 0000-0002-5985-9261
|b 12
700 1 _ |a Krämer, Oliver H
|0 0000-0003-3973-045X
|b 13
773 _ _ |a 10.1002/anie.202514788
|g p. e202514788
|0 PERI:(DE-600)2011836-3
|p nn
|t Angewandte Chemie / International edition
|v nn
|y 2025
|x 1433-7851
909 C O |o oai:inrepo02.dkfz.de:305441
|p VDB
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 7
|6 P:(DE-He78)f08873535c440e3ce033c84d5786f70f
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 8
|6 P:(DE-He78)908367a659dea9e28dac34592b3c46e5
913 1 _ |a DE-HGF
|b Gesundheit
|l Krebsforschung
|1 G:(DE-HGF)POF4-310
|0 G:(DE-HGF)POF4-312
|3 G:(DE-HGF)POF4
|2 G:(DE-HGF)POF4-300
|4 G:(DE-HGF)POF
|v Funktionelle und strukturelle Genomforschung
|x 0
914 1 _ |y 2025
915 _ _ |a Nationallizenz
|0 StatID:(DE-HGF)0420
|2 StatID
|d 2024-12-16
|w ger
915 _ _ |a DEAL Wiley
|0 StatID:(DE-HGF)3001
|2 StatID
|d 2024-12-16
|w ger
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0200
|2 StatID
|b SCOPUS
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0300
|2 StatID
|b Medline
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0199
|2 StatID
|b Clarivate Analytics Master Journal List
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1150
|2 StatID
|b Current Contents - Physical, Chemical and Earth Sciences
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0160
|2 StatID
|b Essential Science Indicators
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1030
|2 StatID
|b Current Contents - Life Sciences
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1200
|2 StatID
|b Chemical Reactions
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1210
|2 StatID
|b Index Chemicus
|d 2024-12-16
915 _ _ |a WoS
|0 StatID:(DE-HGF)0113
|2 StatID
|b Science Citation Index Expanded
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0150
|2 StatID
|b Web of Science Core Collection
|d 2024-12-16
915 _ _ |a JCR
|0 StatID:(DE-HGF)0100
|2 StatID
|b ANGEW CHEM INT EDIT : 2022
|d 2024-12-16
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0600
|2 StatID
|b Ebsco Academic Search
|d 2024-12-16
915 _ _ |a Peer Review
|0 StatID:(DE-HGF)0030
|2 StatID
|b ASC
|d 2024-12-16
915 _ _ |a IF >= 15
|0 StatID:(DE-HGF)9915
|2 StatID
|b ANGEW CHEM INT EDIT : 2022
|d 2024-12-16
920 1 _ |0 I:(DE-He78)B310-20160331
|k B310
|l KKE Pädiatrische Onkologie
|x 0
920 1 _ |0 I:(DE-He78)HD01-20160331
|k HD01
|l DKTK HD zentral
|x 1
980 _ _ |a journal
980 _ _ |a VDB
980 _ _ |a I:(DE-He78)B310-20160331
980 _ _ |a I:(DE-He78)HD01-20160331
980 _ _ |a UNRESTRICTED

LibraryCollectionCLSMajorCLSMinorLanguageAuthor
Marc 21