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| 001 | 300596 | ||
| 005 | 20250427020222.0 | ||
| 024 | 7 | _ | |a 10.1038/s41392-025-02209-8 |2 doi |
| 024 | 7 | _ | |a pmid:40254631 |2 pmid |
| 024 | 7 | _ | |a 2095-9907 |2 ISSN |
| 024 | 7 | _ | |a 2059-3635 |2 ISSN |
| 024 | 7 | _ | |a altmetric:176408222 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2025-00810 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Al Hamwi, Ghazl |b 0 |
| 245 | _ | _ | |a Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models. |
| 260 | _ | _ | |a London |c 2025 |b Macmillan Publishers, part of Springer Nature |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1745329354_26886 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 314 - Immunologie und Krebs (POF4-314) |0 G:(DE-HGF)POF4-314 |c POF4-314 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de |
| 650 | _ | 7 | |a Receptors, G-Protein-Coupled |2 NLM Chemicals |
| 650 | _ | 7 | |a MRGPRX2 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Receptors, Neuropeptide |2 NLM Chemicals |
| 650 | _ | 7 | |a Nerve Tissue Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a beta-Arrestin 2 |2 NLM Chemicals |
| 650 | _ | 7 | |a Mrgprb2 protein, mouse |2 NLM Chemicals |
| 650 | _ | 7 | |a ARRB2 protein, human |2 NLM Chemicals |
| 650 | _ | 2 | |a Mast Cells: drug effects |2 MeSH |
| 650 | _ | 2 | |a Mast Cells: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mast Cells: pathology |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Receptors, G-Protein-Coupled: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Receptors, G-Protein-Coupled: genetics |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a Mice |2 MeSH |
| 650 | _ | 2 | |a Receptors, Neuropeptide: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Receptors, Neuropeptide: genetics |2 MeSH |
| 650 | _ | 2 | |a Nerve Tissue Proteins: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Nerve Tissue Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a beta-Arrestin 2: genetics |2 MeSH |
| 650 | _ | 2 | |a Disease Models, Animal |2 MeSH |
| 700 | 1 | _ | |a Alnouri, Mohamad Wessam |b 1 |
| 700 | 1 | _ | |a Verdonck, Sven |0 0000-0002-6017-2491 |b 2 |
| 700 | 1 | _ | |a Leonczak, Piotr |0 0000-0002-2794-2941 |b 3 |
| 700 | 1 | _ | |a Chaki, Shaswati |0 0000-0002-9696-2786 |b 4 |
| 700 | 1 | _ | |a Frischbutter, Stefan |0 0000-0003-3971-7343 |b 5 |
| 700 | 1 | _ | |a Kolkhir, Pavel |b 6 |
| 700 | 1 | _ | |a Matthey, Michaela |b 7 |
| 700 | 1 | _ | |a Kopp, Constantin |b 8 |
| 700 | 1 | _ | |a Bednarski, Marek |b 9 |
| 700 | 1 | _ | |a Riedel, Yvonne K |b 10 |
| 700 | 1 | _ | |a Marx, Daniel |b 11 |
| 700 | 1 | _ | |a Clemens, Sophie |b 12 |
| 700 | 1 | _ | |a Namasivayam, Vigneshwaran |0 0000-0003-3031-3377 |b 13 |
| 700 | 1 | _ | |a Gattner, Susanne |b 14 |
| 700 | 1 | _ | |a Thimm, Dominik |b 15 |
| 700 | 1 | _ | |a Sylvester, Katharina |b 16 |
| 700 | 1 | _ | |a Wolf, Katharina |0 P:(DE-He78)e107b92b947a96777fe426a2ea115115 |b 17 |u dkfz |
| 700 | 1 | _ | |a Kremer, Andreas E |0 0000-0002-9263-948X |b 18 |
| 700 | 1 | _ | |a De Jonghe, Steven |0 0000-0002-3872-6558 |b 19 |
| 700 | 1 | _ | |a Wenzel, Daniela |b 20 |
| 700 | 1 | _ | |a Kotańska, Magdalena |b 21 |
| 700 | 1 | _ | |a Ali, Hydar |0 0000-0001-9190-1960 |b 22 |
| 700 | 1 | _ | |a Herdewijn, Piet |b 23 |
| 700 | 1 | _ | |a Müller, Christa E |0 0000-0002-0013-6624 |b 24 |
| 773 | _ | _ | |a 10.1038/s41392-025-02209-8 |g Vol. 10, no. 1, p. 128 |0 PERI:(DE-600)2886872-9 |n 1 |p 128 |t Signal transduction and targeted therapy |v 10 |y 2025 |x 2095-9907 |
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