{"id":3789,"date":"2026-07-24T01:09:05","date_gmt":"2026-07-23T16:09:05","guid":{"rendered":"https:\/\/misterx95.myds.me\/wordpress\/?p=3789"},"modified":"2026-07-24T01:09:07","modified_gmt":"2026-07-23T16:09:07","slug":"journal-club-2026-07-24","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=3789","title":{"rendered":"Journal club 2026.07.24"},"content":{"rendered":"\n

Subnanomolar MAS-related G protein-coupled receptor-X2\/B2 antagonists with efficacy in human mast cells and disease models<\/strong><\/h2>\n\n\n\n

Ghazl Al Hamwi1<\/sup>, Mohamad Wessam Alnouri1<\/sup>, Sven Verdonck 2<\/sup>, Piotr Leonczak 2<\/sup>, Shaswati Chaki 3<\/sup>, Stefan Frischbutter 4,5<\/sup>,
Pavel Kolkhir4,5<\/sup>, Michaela Matthey6<\/sup>, Constantin Kopp1<\/sup>, Marek Bednarski7<\/sup>, Yvonne K. Riedel1<\/sup>, Daniel Marx1<\/sup>, Sophie Clemens1<\/sup>,
Vigneshwaran Namasivayam 1<\/sup>, Susanne Gattner1<\/sup>, Dominik Thimm1<\/sup>, Katharina Sylvester1<\/sup>, Katharina Wolf8,9<\/sup>, Andreas E. Kremer 8,10<\/sup>,
Steven De Jonghe 2<\/sup>, Daniela Wenzel6,11<\/sup>, Magdalena Kota\u0144ska7<\/sup>, Hydar Ali 3<\/sup>, Piet Herdewijn2<\/sup> and Christa E. M\u00fcller 1\u2709<\/sup><\/mark><\/p>\n\n\n\n

1<\/sup>PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany; 2<\/sup>Medicinal Chemistry,
Rega Institute for Medical Research, KU Leuven, Herestraat 49-box 1041, 3000 Leuven, Belgium; 3<\/sup>Department of Basic & Translational Sciences, School of Dental Medicine,
University of Pennsylvania, Philadelphia, PA 19104, USA; 4<\/sup>Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and
Humboldt-Universit\u00e4t zu Berlin, 12203 Berlin, Germany; 5<\/sup>Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, 12203 Berlin,
Germany; 6<\/sup>Department of Systems Physiology, Institute of Physiology, Medical Faculty, Ruhr University of Bochum, 44801 Bochum, Germany; 7<\/sup>Department of Pharmacological
Screening, Jagiellonian University, Medical College, Medyczna 9, 30-688 Krakow, Poland; 8<\/sup>Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-
University Erlangen-N\u00fcrnberg, N\u00fcrnberg, Germany; 9<\/sup>Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)\u2014A Helmholtz Institute of the DKFZ, Mainz, Germany;
10<\/sup>Department of Gastroenterology and Hepatology, University Hospital Z\u00fcrich, University of Z\u00fcrich, Z\u00fcrich, Switzerland and 11<\/sup>Institute of Physiology I, Life & Brain Center, Medical
Faculty, University of Bonn, 53127 Bonn, Germany
Correspondence: Christa E M\u00fcller (christa.mueller@uni-bonn.de)
These authors contributed equally: Ghazl Al Hamwi, Mohamad Wessam Alnouri, Sven Verdonck<\/p>\n\n\n\n

Received: 14 August 2024 Revised: 24 February 2025 Accepted: 18 March 2025<\/p>\n\n\n\n

Published online: 21 April 2025<\/p>\n\n\n\n

Abstract<\/h2>\n\n\n\n

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<\/em>] pyrimidin-4(1H<\/em>)-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+<\/sup> mobilization assays (K<\/em>i<\/sub> value 0.142\u2009nM) and was found to block MRGPRX2-mediated G\u03b1q<\/sub> and G\u03b1i1<\/sub> dissociation, in addition to \u03b2<\/em>-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+<\/sup> mobilization assays (K<\/em>i<\/sub> 0.302\u2009nM), 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.<\/p>\n\n\n\n

Signal Transduction and Targeted Therapy<\/em><\/a>\u00a0volume\u00a010<\/strong>, Article\u00a0number:\u00a0128\u00a0(2025)<\/p>\n\n\n\n

https:\/\/doi.org\/10.1038\/s41392-025-02209-8<\/a><\/p>\n\n\n\n

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41392_2025_2209_MOESM1_ESM<\/a>Download<\/a><\/div>\n\n\n\n
41392_2025_2209_MOESM2_ESM<\/a>Download<\/a><\/div>\n\n\n\n
41392_2025_2209_MOESM3_ESM<\/a>Download<\/a><\/div>\n","protected":false},"excerpt":{"rendered":"

Subnanomolar MAS-related G protein-coupled receptor-X2\/B2 antagonists with efficacy in human mast cells and disease models Ghazl Al Hamwi1, Mohamad Wessam Alnouri1, Sven Verdonck 2, Piotr Leonczak 2, Shaswati Chaki 3, Stefan Frischbutter 4,5,Pavel Kolkhir4,5, Michaela Matthey6, Constantin Kopp1, Marek Bednarski7, Yvonne K. Riedel1, Daniel Marx1, Sophie Clemens1,Vigneshwaran Namasivayam 1, Susanne Gattner1, Dominik Thimm1, Katharina Sylvester1, […]<\/p>\n","protected":false},"author":14,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3789"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/14"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3789"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3789\/revisions"}],"predecessor-version":[{"id":3794,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3789\/revisions\/3794"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3789"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3789"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3789"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}