%0 Journal Article
%T Inhibition of Mast Cell Degranulation by Novel Small Molecule MRGPRX2 Antagonists.
%A Wollam J
%A Solomon M
%A Villescaz C
%A Lanier M
%A Evans S
%A Bacon C
%A Freeman D
%A Vasquez A
%A Vest A
%A Napora J
%A Charlot B
%A Cavarlez C
%A Kim A
%A Dvorak L
%A Selfridge B
%A Huang L
%A Nevarez A
%A Dedman H
%A Brooks J
%A Frischbutter S
%A Metz M
%A Serhan N
%A Gaudenzio N
%A Timony G
%A Martinborough E
%A Boehm MF
%A Viswanath V
%J J Allergy Clin Immunol
%V 0
%N 0
%D 2024 Jul 4
%M 38971540
%F 14.29
%R 10.1016/j.jaci.2024.07.002
%X <B>BACKGROUND: </B>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.<BR><B>OBJECTIVE: </B>We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease.<BR><B>METHODS: </B>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 Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) 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.<BR><B>RESULTS: </B>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 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin.<BR><B>CONCLUSIONS: </B>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.