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. 2024 Oct;154(4):1033-1043.
doi: 10.1016/j.jaci.2024.07.002. Epub 2024 Jul 5.

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists

Joshua Wollam  1 , Michelle Solomon  1 , Christiane Villescaz  1 , Marion Lanier  1 , Samantha Evans  1 , Corinne Bacon  1 , David Freeman  1 , Alexis Vasquez  1 , Alan Vest  1 , Jim Napora  1 , Brittney Charlot  1 , Christine Cavarlez  1 , Andrew Kim  1 , Lisa Dvorak  1 , Brandon Selfridge  1 , Liming Huang  1 , Andres Nevarez  1 , Harry Dedman  1 , Jennifer Brooks  1 , Stefan Frischbutter  2 , Martin Metz  2 , Nadine Serhan  3 , Nicolas Gaudenzio  4 , Gregg Timony  1 , Esther Martinborough  1 , Marcus F Boehm  1 , Veena Viswanath  5
Affiliations
Free article

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists

Joshua Wollam et al. J Allergy Clin Immunol. 2024 Oct.
Free article

Abstract

Background: 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(-/-) 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 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.

Conclusions: 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.

Keywords: IgE independent; Inflammation; degranulation; mast cells; neuropeptides; sensory neurons; skin; urticaria.

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Conflict of interest statement

Disclosure statement This work was funded by Escient Pharmaceuticals. Disclosure of potential conflicts of interest: J. Wollam, M. Solomon, C. Villescaz, M. Lanier, A. Vest, J. Napora, B. Charlot, C. Cavarlez, S. Evans, C. Bacon, A. Vasquez, D. Freeman, A. Kim, L. Dvorak, B. Selfridge, L. Huang, A. Nevarez, H. Dedman, J. Brooks, G. Timony, E. Martinborough, M. F. Boehm, and V. Viswanath are employees of Escient Pharmaceuticals and hold stock in the company. S. Frischbutter has received research funding from Escient Pharmaceuticals. M. Metz has received honoraria as a consultant for Escient Pharmaceuticals. N. Gaudenzio has a patent entitled “Method to treat type 2 inflammation or mast-cell dependent disease” (WO2020229648A1), acts as a scientific consultant for Escient Pharmaceuticals, and acts as Chief Scientific Officer and is a shareholder at Genoskin. N. Serhan declares that they have no relevant conflicts of interest.

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