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@ARTICLE{Narayanan:484604,
      author       = {Narayanan, Dilip and Tran, Kim T. and Pallesen, Jakob S.
                      and Solbak, Sara M. Ø. and Qin, Yuting and Mukminova, Elina
                      and Luchini, Martina and Vasilyeva, Kristina O. and
                      González Chichón, Dorleta and Goutsiou, Georgia and
                      Poulsen, Cecilie and Haapanen, Nanna and Popowicz, Grzegorz
                      M. and Sattler, Michael and Olagnier, David and Gajhede,
                      Michael and Bach, Anders},
      title        = {{D}evelopment of {N}oncovalent {S}mall-{M}olecule
                      {K}eap1-{N}rf2 {I}nhibitors by {F}ragment-{B}ased {D}rug
                      {D}iscovery},
      journal      = {Journal of medicinal chemistry},
      volume       = {65},
      number       = {21},
      issn         = {0022-2623},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {PUBDB-2022-06371},
      pages        = {14481 - 14526},
      year         = {2022},
      note         = {Waiting for fulltext},
      abstract     = {Targeting the protein–protein interaction (PPI) between
                      the transcription factor nuclear factor erythroid 2-related
                      factor 2 (Nrf2) and its repressor, Kelch-like ECH-associated
                      protein 1 (Keap1), constitutes a promising strategy for
                      treating diseases involving oxidative stress and
                      inflammation. Here, a fragment-based drug discovery (FBDD)
                      campaign resulted in novel, high-affinity (K$_i$ = 280 nM),
                      and cell-active noncovalent small-molecule Keap1-Nrf2 PPI
                      inhibitors. We screened 2500 fragments using orthogonal
                      assays─fluorescence polarization (FP), thermal shift assay
                      (TSA), and surface plasmon resonance (SPR)─and validated
                      the hits by saturation transfer difference (STD) NMR,
                      leading to 28 high-priority hits. Thirteen co-structures
                      showed fragments binding mainly in the P4 and P5 subpockets
                      of Keap1’s Kelch domain, and three fluorenone-based
                      fragments featuring a novel binding mode were optimized by
                      structure-based drug discovery. We thereby disclose several
                      fragment hits, including their binding modes, and show how
                      FBDD can be performed to find new small-molecule Keap1-Nrf2
                      PPI inhibitors.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P13-20150101 / EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36263945},
      UT           = {WOS:000885322600001},
      doi          = {10.1021/acs.jmedchem.2c00830},
      url          = {https://bib-pubdb1.desy.de/record/484604},
}