Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models

Al Hamwi G, Alnouri MW, Verdonck S, Leonczak P, Chaki S, Frischbutter S, Kolkhir P, Matthey M, Kopp C, Bednarski M, Riedel YK, Marx D, Clemens S, Namasivayam V, Gattner S, Thimm D, Sylvester K, Wolf K, Kremer A, De Jonghe S, Wenzel D, Kotańska M, Ali H, Herdewijn P, Müller CE (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Signal Transduction and Targeted Therapy Springer Nature

Book Volume: 10

Article Number: 128

Journal Issue: 1

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.

Authors with CRIS profile

Katharina Wolf Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Rega Institute for Medical Research BE Belgium (BE) University of Pennsylvania (UPenn) US United States (USA) (US) Charité - Universitätsmedizin Berlin DE Germany (DE) Ruhr-Universität Bochum (RUB) DE Germany (DE) Jagiellonian University Medical College PL Poland (PL)

How to cite

APA:

Al Hamwi, G., Alnouri, M.W., Verdonck, S., Leonczak, P., Chaki, S., Frischbutter, S.,... Müller, C.E. (2025). Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models. Signal Transduction and Targeted Therapy, 10(1). https://doi.org/10.1038/s41392-025-02209-8

MLA:

Al Hamwi, Ghazl, et al. "Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models." Signal Transduction and Targeted Therapy 10.1 (2025).

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