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@ARTICLE{Wydra:301539,
      author       = {V. R. Wydra and N. Plank and S. Zwirner and R. Selig and A.
                      Rasch and B. Masberg and M. Lämmerhofer and L. Zender$^*$
                      and P. Koch and W. Albrecht and S. Laufer$^*$},
      title        = {{A} '{L}igand {F}irst' {A}pproach toward {S}elective,
                      {C}ovalent {JNK}2/3 {I}nhibitors.},
      journal      = {Journal of medicinal chemistry},
      volume       = {68},
      number       = {11},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2025-01060},
      pages        = {12004-12028},
      year         = {2025},
      note         = {2025 Jun 12;68(11):12004-12028},
      abstract     = {All JNK isoforms play a specific role in various diseases.
                      The role of the JNK2 isoform has so far received little
                      attention compared to its JNK1 and JNK3 counterparts with
                      JNK3 being a potential target for neurodegenerative diseases
                      and an inhibitor with JNK1 bias being currently investigated
                      in clinical trials. Using an iterative, structure-guided
                      optimization approach starting from a reported reversible
                      binding aminopyrazole-derived scaffold, novel highly potent
                      JNK2/3 selective inhibitors were generated ('ligand-first
                      approach'). These reversible inhibitors were further
                      transformed to covalent inhibitors by attaching an
                      electrophilic warhead moiety, able to address a conserved
                      cysteine side chain present in JNKs. Reversible and covalent
                      inhibitors presented in this study show high JNK2/3 isoform
                      selectivity and activity in cells. The covalently acting
                      lead compound 56d shows good kinetic data with a kinact/KI
                      (JNK2) = 38,200 M-1 s-1 as well as cellular isoform
                      selectivity and a clean kinome profile.},
      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:40404564},
      doi          = {10.1021/acs.jmedchem.5c00884},
      url          = {https://inrepo02.dkfz.de/record/301539},
}