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@ARTICLE{AlHamwi:300596,
      author       = {G. Al Hamwi and M. W. Alnouri and S. Verdonck and P.
                      Leonczak and S. Chaki and S. Frischbutter and P. Kolkhir and
                      M. Matthey and C. Kopp and M. Bednarski and Y. K. Riedel and
                      D. Marx and S. Clemens and V. Namasivayam and S. Gattner and
                      D. Thimm and K. Sylvester and K. Wolf$^*$ and A. E. Kremer
                      and S. De Jonghe and D. Wenzel and M. Kotańska and H. Ali
                      and P. Herdewijn and C. E. Müller},
      title        = {{S}ubnanomolar {MAS}-related {G} protein-coupled
                      receptor-{X}2/{B}2 antagonists with efficacy in human mast
                      cells and disease models.},
      journal      = {Signal transduction and targeted therapy},
      volume       = {10},
      number       = {1},
      issn         = {2095-9907},
      address      = {London},
      publisher    = {Macmillan Publishers, part of Springer Nature},
      reportid     = {DKFZ-2025-00810},
      pages        = {128},
      year         = {2025},
      abstract     = {The MAS-related G protein-coupled receptor-X2 (MRGPRX2), an
                      orphan receptor expressed on mast cells (MCs), is
                      upregulated upon inflammation and induces hypersensitivity
                      and inflammatory diseases. In contrast to the large number
                      of MRGPRX2 agonists, only a few antagonists have been
                      described, and no optimization has been reported to improve
                      potency, selectivity, and drug-like properties. Antagonists
                      with ancillary inhibition of the putative mouse ortholog
                      MRGPRB2 have not been described. Here, we present a
                      multi-disciplinary approach involving chemistry, biology,
                      and computational science, resulting in the development of a
                      small-molecule MRGPRX2 antagonist (PSB-172656,
                      3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo [1,2-a]
                      pyrimidin-4(1H)-one) based on a fragment screening hit. The
                      compound exhibits metabolic stability, low cytotoxicity, and
                      competitive blockade of MRGPRX2 activation induced by a
                      diverse range of agonists. It displays subnanomolar potency
                      in Ca2+ mobilization assays (Ki value 0.142 nM) and was
                      found to block MRGPRX2-mediated Gαq and Gαi1 dissociation,
                      in addition to β-arrestin-2 recruitment. PSB-172656 is
                      selective for MRGPRX2 versus all other MRGPRX subtypes. Its
                      effect on MCs was confirmed in cell lines, including rat
                      basophilic leukemia cells (RBL-2H3) recombinantly expressing
                      human MRGPRX2, human Laboratory of Allergic Diseases 2
                      (LAD2) MCs, and native human skin MCs. PSB-172656 was found
                      to additionally block the putative mouse ortholog of
                      MRGPRX2, MRGPRB2, as determined in Ca2+ mobilization assays
                      (Ki 0.302 nM), and to prevent mouse tracheal contractions,
                      local allergic reactions, and systemic anaphylactic
                      symptoms. PSB-172656 constitutes a unique pharmacological
                      tool and has the potential to be developed as a drug for
                      mast cell-mediated hypersensitivity reactions and chronic
                      inflammatory diseases, addressing a huge unmet medical
                      need.},
      keywords     = {Mast Cells: drug effects / Mast Cells: metabolism / Mast
                      Cells: pathology / Humans / Receptors, G-Protein-Coupled:
                      antagonists $\&$ inhibitors / Receptors, G-Protein-Coupled:
                      genetics / Animals / Mice / Receptors, Neuropeptide:
                      antagonists $\&$ inhibitors / Receptors, Neuropeptide:
                      genetics / Nerve Tissue Proteins: antagonists $\&$
                      inhibitors / Nerve Tissue Proteins: genetics / beta-Arrestin
                      2: genetics / Disease Models, Animal / Receptors,
                      G-Protein-Coupled (NLM Chemicals) / MRGPRX2 protein, human
                      (NLM Chemicals) / Receptors, Neuropeptide (NLM Chemicals) /
                      Nerve Tissue Proteins (NLM Chemicals) / beta-Arrestin 2 (NLM
                      Chemicals) / Mrgprb2 protein, mouse (NLM Chemicals) / ARRB2
                      protein, human (NLM Chemicals)},
      cin          = {D190},
      ddc          = {610},
      cid          = {I:(DE-He78)D190-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40254631},
      doi          = {10.1038/s41392-025-02209-8},
      url          = {https://inrepo02.dkfz.de/record/300596},
}