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@ARTICLE{Rak:275604,
      author       = {M. Rak and R. Tesch and L. M. Berger and E. Shevchenko and
                      M. Raab and A. Tjaden and R. Zhubi and D.-I. Balourdas and
                      A. C. Joerger and A. Poso and A. Krämer$^*$ and L. Elson
                      and A. Lučić and T. Kronenberger and T. Hanke and K.
                      Strebhardt and M. Sanhaji and S. Knapp$^*$},
      title        = {{S}hifting the selectivity of
                      pyrido[2,3-d]pyrimidin-7(8{H})-one inhibitors towards the
                      salt-inducible kinase ({SIK}) subfamily.},
      journal      = {European journal of medicinal chemistry},
      volume       = {254},
      issn         = {0009-4374},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2023-00814},
      pages        = {115347},
      year         = {2023},
      abstract     = {Salt-inducible kinases 1-3 (SIK1-3) are key regulators of
                      the LKB1-AMPK pathway and play an important role in cellular
                      homeostasis. Dysregulation of any of the three isoforms has
                      been associated with tumorigenesis in liver, breast, and
                      ovarian cancers. We have recently developed the dual
                      pan-SIK/group I p21-activated kinase (PAK) chemical probe
                      MRIA9. However, inhibition of p21-activated kinases has been
                      associated with cardiotoxicity in vivo, which complicates
                      the use of MRIA9 as a tool compound. Here, we present a
                      structure-based approach involving the back-pocket and
                      gatekeeper residues, for narrowing the selectivity of
                      pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards
                      SIK kinases, eliminating PAK activity. Optimization was
                      guided by high-resolution crystal structure analysis and
                      computational methods, resulting in a pan-SIK inhibitor,
                      MR22, which no longer exhibited activity on STE group
                      kinases and displayed excellent selectivity in a
                      representative kinase panel. MR22-dependent SIK inhibition
                      led to centrosome dissociation and subsequent cell-cycle
                      arrest in ovarian cancer cells, as observed with MRIA9,
                      conclusively linking these phenotypic effects to SIK
                      inhibition. Taken together, MR22 represents a valuable tool
                      compound for studying SIK kinase function in cells.},
      keywords     = {Kinase inhibitor (Other) / MR22 (Other) / MRIA9 (Other) /
                      SIK (Other) / Salt-inducible kinase (Other) /
                      pyrido[2,3-d]pyrimidin-7(8H)-one (Other)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37094449},
      doi          = {10.1016/j.ejmech.2023.115347},
      url          = {https://inrepo02.dkfz.de/record/275604},
}