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Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists.

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists.

Authors :
Wollam, Joshua
Solomon, Michelle
Villescaz, Christiane
Lanier, Marion
Evans, Samantha
Bacon, Corinne
Freeman, David
Vasquez, Alexis
Vest, Alan
Napora, Jim
Charlot, Brittney
Cavarlez, Christine
Kim, Andrew
Dvorak, Lisa
Selfridge, Brandon
Huang, Liming
Nevarez, Andres
Dedman, Harry
Brooks, Jennifer
Frischbutter, Stefan
Source :
Journal of Allergy & Clinical Immunology; Oct2024, Vol. 154 Issue 4, p1033-1043, 11p
Publication Year :
2024

Abstract

Mas-related G protein–coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell–mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell–mediated disease. Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell–derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2 <superscript> em(−/−) </superscript> knockout and Mrgprb2 <superscript> em(MRGPRX2) </superscript> transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00916749
Volume :
154
Issue :
4
Database :
Supplemental Index
Journal :
Journal of Allergy & Clinical Immunology
Publication Type :
Academic Journal
Accession number :
179796912
Full Text :
https://doi.org/10.1016/j.jaci.2024.07.002