TY  - JOUR
AU  - Al Hamwi, Ghazl
AU  - Alnouri, Mohamad Wessam
AU  - Verdonck, Sven
AU  - Leonczak, Piotr
AU  - Chaki, Shaswati
AU  - Frischbutter, Stefan
AU  - Kolkhir, Pavel
AU  - Matthey, Michaela
AU  - Kopp, Constantin
AU  - Bednarski, Marek
AU  - Riedel, Yvonne K
AU  - Marx, Daniel
AU  - Clemens, Sophie
AU  - Namasivayam, Vigneshwaran
AU  - Gattner, Susanne
AU  - Thimm, Dominik
AU  - Sylvester, Katharina
AU  - Wolf, Katharina
AU  - Kremer, Andreas E
AU  - De Jonghe, Steven
AU  - Wenzel, Daniela
AU  - Kotańska, Magdalena
AU  - Ali, Hydar
AU  - Herdewijn, Piet
AU  - Müller, Christa E
TI  - Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models.
JO  - Signal transduction and targeted therapy
VL  - 10
IS  - 1
SN  - 2095-9907
CY  - London
PB  - Macmillan Publishers, part of Springer Nature
M1  - DKFZ-2025-00810
SP  - 128
PY  - 2025
AB  - 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.
KW  - Mast Cells: drug effects
KW  - Mast Cells: metabolism
KW  - Mast Cells: pathology
KW  - Humans
KW  - Receptors, G-Protein-Coupled: antagonists & inhibitors
KW  - Receptors, G-Protein-Coupled: genetics
KW  - Animals
KW  - Mice
KW  - Receptors, Neuropeptide: antagonists & inhibitors
KW  - Receptors, Neuropeptide: genetics
KW  - Nerve Tissue Proteins: antagonists & inhibitors
KW  - Nerve Tissue Proteins: genetics
KW  - beta-Arrestin 2: genetics
KW  - Disease Models, Animal
KW  - Receptors, G-Protein-Coupled (NLM Chemicals)
KW  - MRGPRX2 protein, human (NLM Chemicals)
KW  - Receptors, Neuropeptide (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - beta-Arrestin 2 (NLM Chemicals)
KW  - Mrgprb2 protein, mouse (NLM Chemicals)
KW  - ARRB2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40254631
DO  - DOI:10.1038/s41392-025-02209-8
UR  - https://inrepo02.dkfz.de/record/300596
ER  -