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000300596 1001_ $$aAl Hamwi, Ghazl$$b0
000300596 245__ $$aSubnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models.
000300596 260__ $$aLondon$$bMacmillan Publishers, part of Springer Nature$$c2025
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000300596 520__ $$aThe MAS-related G protein-coupled receptor-X2 (MRGPRX2), an orphan receptor expressed on mast cells (MCs), is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases. In contrast to the large number of MRGPRX2 agonists, only a few antagonists have been described, and no optimization has been reported to improve potency, selectivity, and drug-like properties. Antagonists with ancillary inhibition of the putative mouse ortholog MRGPRB2 have not been described. Here, we present a multi-disciplinary approach involving chemistry, biology, and computational science, resulting in the development of a small-molecule MRGPRX2 antagonist (PSB-172656, 3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo [1,2-a] pyrimidin-4(1H)-one) based on a fragment screening hit. The compound exhibits metabolic stability, low cytotoxicity, and competitive blockade of MRGPRX2 activation induced by a diverse range of agonists. It displays subnanomolar potency in Ca2+ mobilization assays (Ki value 0.142 nM) and was found to block MRGPRX2-mediated Gαq and Gαi1 dissociation, in addition to β-arrestin-2 recruitment. PSB-172656 is selective for MRGPRX2 versus all other MRGPRX subtypes. Its effect on MCs was confirmed in cell lines, including rat basophilic leukemia cells (RBL-2H3) recombinantly expressing human MRGPRX2, human Laboratory of Allergic Diseases 2 (LAD2) MCs, and native human skin MCs. PSB-172656 was found to additionally block the putative mouse ortholog of MRGPRX2, MRGPRB2, as determined in Ca2+ mobilization assays (Ki 0.302 nM), and to prevent mouse tracheal contractions, local allergic reactions, and systemic anaphylactic symptoms. PSB-172656 constitutes a unique pharmacological tool and has the potential to be developed as a drug for mast cell-mediated hypersensitivity reactions and chronic inflammatory diseases, addressing a huge unmet medical need.
000300596 536__ $$0G:(DE-HGF)POF4-314$$a314 - Immunologie und Krebs (POF4-314)$$cPOF4-314$$fPOF IV$$x0
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000300596 650_7 $$2NLM Chemicals$$aReceptors, G-Protein-Coupled
000300596 650_7 $$2NLM Chemicals$$aMRGPRX2 protein, human
000300596 650_7 $$2NLM Chemicals$$aReceptors, Neuropeptide
000300596 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000300596 650_7 $$2NLM Chemicals$$abeta-Arrestin 2
000300596 650_7 $$2NLM Chemicals$$aMrgprb2 protein, mouse
000300596 650_7 $$2NLM Chemicals$$aARRB2 protein, human
000300596 650_2 $$2MeSH$$aMast Cells: drug effects
000300596 650_2 $$2MeSH$$aMast Cells: metabolism
000300596 650_2 $$2MeSH$$aMast Cells: pathology
000300596 650_2 $$2MeSH$$aHumans
000300596 650_2 $$2MeSH$$aReceptors, G-Protein-Coupled: antagonists & inhibitors
000300596 650_2 $$2MeSH$$aReceptors, G-Protein-Coupled: genetics
000300596 650_2 $$2MeSH$$aAnimals
000300596 650_2 $$2MeSH$$aMice
000300596 650_2 $$2MeSH$$aReceptors, Neuropeptide: antagonists & inhibitors
000300596 650_2 $$2MeSH$$aReceptors, Neuropeptide: genetics
000300596 650_2 $$2MeSH$$aNerve Tissue Proteins: antagonists & inhibitors
000300596 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000300596 650_2 $$2MeSH$$abeta-Arrestin 2: genetics
000300596 650_2 $$2MeSH$$aDisease Models, Animal
000300596 7001_ $$aAlnouri, Mohamad Wessam$$b1
000300596 7001_ $$00000-0002-6017-2491$$aVerdonck, Sven$$b2
000300596 7001_ $$00000-0002-2794-2941$$aLeonczak, Piotr$$b3
000300596 7001_ $$00000-0002-9696-2786$$aChaki, Shaswati$$b4
000300596 7001_ $$00000-0003-3971-7343$$aFrischbutter, Stefan$$b5
000300596 7001_ $$aKolkhir, Pavel$$b6
000300596 7001_ $$aMatthey, Michaela$$b7
000300596 7001_ $$aKopp, Constantin$$b8
000300596 7001_ $$aBednarski, Marek$$b9
000300596 7001_ $$aRiedel, Yvonne K$$b10
000300596 7001_ $$aMarx, Daniel$$b11
000300596 7001_ $$aClemens, Sophie$$b12
000300596 7001_ $$00000-0003-3031-3377$$aNamasivayam, Vigneshwaran$$b13
000300596 7001_ $$aGattner, Susanne$$b14
000300596 7001_ $$aThimm, Dominik$$b15
000300596 7001_ $$aSylvester, Katharina$$b16
000300596 7001_ $$0P:(DE-He78)e107b92b947a96777fe426a2ea115115$$aWolf, Katharina$$b17$$udkfz
000300596 7001_ $$00000-0002-9263-948X$$aKremer, Andreas E$$b18
000300596 7001_ $$00000-0002-3872-6558$$aDe Jonghe, Steven$$b19
000300596 7001_ $$aWenzel, Daniela$$b20
000300596 7001_ $$aKotańska, Magdalena$$b21
000300596 7001_ $$00000-0001-9190-1960$$aAli, Hydar$$b22
000300596 7001_ $$aHerdewijn, Piet$$b23
000300596 7001_ $$00000-0002-0013-6624$$aMüller, Christa E$$b24
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