Journal Article

DKFZ-2025-00810

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models.

Al Hamwi, G. ; Alnouri, M. W. ; Verdonck, S. ; Leonczak, P. ; Chaki, S. ; Frischbutter, S. ; Kolkhir, P. ; Matthey, M. ; Kopp, C. ; Bednarski, M. ; Riedel, Y. K. ; Marx, D. ; Clemens, S. ; Namasivayam, V. ; Gattner, S. ; Thimm, D. ; Sylvester, K. ; Wolf, K.DKFZ* ; Kremer, A. E. ; De Jonghe, S. ; Wenzel, D. ; Kotańska, M. ; Ali, H. ; Herdewijn, P. ; Müller, C. E.

2025
Macmillan Publishers, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41392-025-02209-8

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.

Keyword(s): Mast Cells: drug effects (MeSH) ; Mast Cells: metabolism (MeSH) ; Mast Cells: pathology (MeSH) ; Humans (MeSH) ; Receptors, G-Protein-Coupled: antagonists & inhibitors (MeSH) ; Receptors, G-Protein-Coupled: genetics (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Receptors, Neuropeptide: antagonists & inhibitors (MeSH) ; Receptors, Neuropeptide: genetics (MeSH) ; Nerve Tissue Proteins: antagonists & inhibitors (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; beta-Arrestin 2: genetics (MeSH) ; Disease Models, Animal (MeSH) ; Receptors, G-Protein-Coupled ; MRGPRX2 protein, human ; Receptors, Neuropeptide ; Nerve Tissue Proteins ; beta-Arrestin 2 ; Mrgprb2 protein, mouse ; ARRB2 protein, human

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Contributing Institute(s):

1. HI-TRON zentral (D190)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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