%0 Journal Article
%A Al Hamwi, Ghazl
%A Alnouri, Mohamad Wessam
%A Verdonck, Sven
%A Leonczak, Piotr
%A Chaki, Shaswati
%A Frischbutter, Stefan
%A Kolkhir, Pavel
%A Matthey, Michaela
%A Kopp, Constantin
%A Bednarski, Marek
%A Riedel, Yvonne K
%A Marx, Daniel
%A Clemens, Sophie
%A Namasivayam, Vigneshwaran
%A Gattner, Susanne
%A Thimm, Dominik
%A Sylvester, Katharina
%A Wolf, Katharina
%A Kremer, Andreas E
%A De Jonghe, Steven
%A Wenzel, Daniela
%A Kotańska, Magdalena
%A Ali, Hydar
%A Herdewijn, Piet
%A Müller, Christa E
%T Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models.
%J Signal transduction and targeted therapy
%V 10
%N 1
%@ 2095-9907
%C London
%I Macmillan Publishers, part of Springer Nature
%M DKFZ-2025-00810
%P 128
%D 2025
%X 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.
%K Mast Cells: drug effects
%K Mast Cells: metabolism
%K Mast Cells: pathology
%K Humans
%K Receptors, G-Protein-Coupled: antagonists & inhibitors
%K Receptors, G-Protein-Coupled: genetics
%K Animals
%K Mice
%K Receptors, Neuropeptide: antagonists & inhibitors
%K Receptors, Neuropeptide: genetics
%K Nerve Tissue Proteins: antagonists & inhibitors
%K Nerve Tissue Proteins: genetics
%K beta-Arrestin 2: genetics
%K Disease Models, Animal
%K Receptors, G-Protein-Coupled (NLM Chemicals)
%K MRGPRX2 protein, human (NLM Chemicals)
%K Receptors, Neuropeptide (NLM Chemicals)
%K Nerve Tissue Proteins (NLM Chemicals)
%K beta-Arrestin 2 (NLM Chemicals)
%K Mrgprb2 protein, mouse (NLM Chemicals)
%K ARRB2 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40254631
%R 10.1038/s41392-025-02209-8
%U https://inrepo02.dkfz.de/record/300596