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@ARTICLE{Ashry:305441,
      author       = {R. Ashry and M. Abdelsalam and J. Hausen and C. Hieber and
                      Y. Zeyn and A.-C. Sarnow and M. Schmidt and S. Najafi$^*$
                      and I. Oehme$^*$ and M. Bros and J.-X. Chen and M. Dejung
                      and W. Sippl and O. H. Krämer},
      title        = {{I}dentification of a {P}roteolysis-{T}argeting-{C}himera
                      that {A}ddresses {A}ctivated {C}heckpoint {K}inase-1
                      {R}eveals its {N}on-{C}atalytic {F}unctions in {T}umor
                      {C}ells.},
      journal      = {Angewandte Chemie / International edition},
      volume       = {nn},
      issn         = {1433-7851},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DKFZ-2025-02159},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      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
                      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.},
      keywords     = {CHK1 (Other) / Cancer cells (Other) / Cereblon (Other) /
                      DNA replication stress (Other) / PROTAC (Other)},
      cin          = {B310 / HD01},
      ddc          = {540},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41104666},
      doi          = {10.1002/anie.202514788},
      url          = {https://inrepo02.dkfz.de/record/305441},
}