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@ARTICLE{Bach:1037154,
      author       = {Bach, Kathrin and Dohnálek, Jan and Škerlová, Jana and
                      Kuzmík, Ján and Poláchová, Edita and Stanchev, Stancho
                      and Majer, Pavel and Fanfrlík, Jindřich and Pecina, Adam
                      and Řezáč, Jan and Lepšík, Martin and Borshchevskiy,
                      Valentin and Polovinkin, Vitaly and Strisovsky, Kvido},
      title        = {{E}xtensive targeting of chemical space at the prime side
                      of ketoamide inhibitors of rhomboid proteases by branched
                      substituents empowers their selectivity and potency},
      journal      = {European journal of medicinal chemistry},
      volume       = {275},
      issn         = {0009-4374},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {FZJ-2025-00499},
      pages        = {116606 -},
      year         = {2024},
      abstract     = {Rhomboid intramembrane serine proteases have been
                      implicated in several pathologies, and emerge as attractive
                      pharmacological target candidates. The most potent and
                      selective rhomboid inhibitors available to date are peptidyl
                      α-ketoamides, but their selectivity for diverse rhomboid
                      proteases and strategies to modulate it in relevant contexts
                      are poorly understood. This gap, together with the lack of
                      suitable in vitro models, hinders ketoamide development for
                      relevant eukaryotic rhomboid enzymes. Here we explore the
                      structure-activity relationship principles of rhomboid
                      inhibiting ketoamides by medicinal chemistry and enzymatic
                      in vitro and in-cell assays with recombinant rhomboid
                      proteases GlpG, human mitochondrial rhomboid PARL and human
                      RHBDL2. We use X-ray crystallography in lipidic cubic phase
                      to understand the binding mode of one of the best ketoamide
                      inhibitors synthesized here containing a branched terminal
                      substituent bound to GlpG. In addition, to extend the
                      interpretation of the co-crystal structure, we use quantum
                      mechanical calculations and quantify the relative importance
                      of interactions along the inhibitor molecule. These combined
                      experimental analyses implicates that more extensive
                      exploration of chemical space at the prime side is
                      unexpectedly powerful for the selectivity of rhomboid
                      inhibiting ketoamides. Together with variations in the
                      peptide sequence at the non-prime side, or its non-peptidic
                      alternatives, this strategy enables targeted tailoring of
                      potent and selective ketoamides towards diverse rhomboid
                      proteases including disease-relevant ones such as PARL and
                      RHBDL2.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {38901105},
      UT           = {WOS:001347413400001},
      doi          = {10.1016/j.ejmech.2024.116606},
      url          = {https://juser.fz-juelich.de/record/1037154},
}