Novel Small Molecule Antagonists Targeting MRGPRX2 Inhibit Mast Cell Degranulation

Summary: This study investigates the development of novel small molecule antagonists that inhibit MRGPRX2-mediated mast cell degranulation. MRGPRX2 is implicated in various mast cell-mediated conditions like chronic urticaria and atopic dermatitis. The study demonstrates the efficacy of these antagonists in reducing mast cell activation in vitro, in vivo, and ex vivo, offering potential therapeutic applications for inflammatory and pain disorders. These antagonists could address conditions that are less responsive to IgE-based treatments.

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. Objective: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell–mediated disease. Methods: 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(2/2) knockout and Mrgprb2em(MRGPRX2) 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. Results: MRGPRX2 antagonists potently inhibited agonistinduced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonistinduced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment

References: Wollam, J., et al. (2024). Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists. J Allergy Clin Immunol. DOI: 10.1016/j.jaci.2024.07.002.