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@ARTICLE{Katzengruber:302838,
      author       = {L. Katzengruber and P. Sander and S. Zwirner and A. Rasch
                      and E. Eberlein and R. Selig and W. Albrecht and L.
                      Zender$^*$ and S. A. Laufer$^*$},
      title        = {{D}iscovery of the {F}irst {H}ighly {S}elective
                      1,4-dihydropyrido[3,4-b]pyrazin-3(2{H})-one {MKK}4
                      {I}nhibitor.},
      journal      = {Journal of medicinal chemistry},
      volume       = {68},
      number       = {14},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2025-01378},
      pages        = {14782-14805},
      year         = {2025},
      note         = {2025 Jul 24;68(14):14782-14805},
      abstract     = {Due to limited treatment options, liver failure remains a
                      major challenge in modern medicine. With the validation of
                      mitogen-activated protein kinase kinase 4 (MKK4, also known
                      as MEK4 or MAP2K4) as a regulator of hepatocyte
                      regeneration, a promising target for curative treatment of
                      degenerative liver diseases was recently identified via in
                      vivo RNAi experiments. The field of small molecules
                      targeting MKK4 is of growing interest. Several MKK4
                      inhibitors with differing scaffolds are known, but few have
                      reasonable selectivity profiles and drug-like properties. To
                      further explore the space of drug-like MKK4 scaffolds, we
                      performed a broad screening campaign and identified BI-D1870
                      as a promising candidate. The dihydropteridinone BI-D1870 is
                      an unselective ribosomal S6 kinase inhibitor with broad
                      off-target activity. In the study presented herein, we
                      report a successful off-to-on target strategy that led to
                      the development of highly selective
                      1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one inhibitors of
                      MKK4.},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40643363},
      doi          = {10.1021/acs.jmedchem.5c00919},
      url          = {https://inrepo02.dkfz.de/record/302838},
}