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@ARTICLE{Wirawan:638310,
      author       = {Wirawan, Ricky and Frei, Matthias and Heider, Anna and
                      Papenkordt, Niklas and Friedrich, Florian and Wein, Thomas
                      and Jung, Manfred and Groll, Michael and Huber, Eva and
                      Bracher, Franz},
      title        = {{T}ailored {S}ir{R}eal-type inhibitors enhance {SIRT}2
                      inhibition through ligand stabilization and disruption of
                      {NAD}$^+$ co-factor binding},
      journal      = {RSC medicinal chemistry},
      volume       = {16},
      number       = {11},
      issn         = {2040-2503},
      address      = {Cambridge},
      publisher    = {Royal Society of Chemistry},
      reportid     = {PUBDB-2025-04028},
      pages        = {5419 - 5440},
      year         = {2025},
      note         = {ISSN 2632-8682 not unique: **2 hits**.},
      abstract     = {Human sirtuin 2 (SIRT2) is an NAD+ dependant enzyme that
                      has been linked to the pathogenesis of various diseases,
                      making it a promising target for pharmaceutical
                      intervention. This study presents a systematic investigation
                      on the inhibitory effects of SIRT2 inhibitors functionalized
                      with diverse electrophilic functional groups. Guided by
                      initial docking studies, we designed and synthesised 14
                      derivatives of two published potent lead structures 24a and
                      SirReal2. The most potent and subtype selective SIRT2
                      inhibitor 29 (RW-78) exhibits an IC50 of 26 nM, which
                      outperforms its lead structure 24a (IC50 = 79 nM) by a
                      factor of 3. The increased potency of 29 is explained by
                      halogen–π interactions with SIRT2 residues as visualized
                      by X-ray crystallography. Furthermore, 29 interferes with
                      NAD+ binding, highlighting co-factor displacement as a valid
                      strategy to inhibit SIRT2. Additionally, we showed cellular
                      target engagement via NanoBRET assays in HEK293T cells (EC50
                      = 15 nM). Altogether our findings provide a deeper insight
                      into the structure–activity relationships of these
                      SirReal-type inhibitors and offer new avenues for
                      optimisation of SIRT2 inhibitors.},
      cin          = {EMBL-User},
      ddc          = {540},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3) / DFG project 503267011 -
                      Sirtuin2 (Sirt2)-Liganden als Hemmstoffe der Desacylierung
                      langkettiger Acyllysine und chemische Sonden für
                      induzierten Proteinabbau (503267011) / DFG project
                      G:(GEPRIS)325871075 - SFB 1309: Chemische Biologie
                      epigenetischer Modifikationen (325871075)},
      pid          = {G:(DE-HGF)POF4-6G3 / G:(GEPRIS)503267011 /
                      G:(GEPRIS)325871075},
      experiment   = {EXP:(DE-H253)P-P13-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1039/D5MD00144G},
      url          = {https://bib-pubdb1.desy.de/record/638310},
}