Tu122 - EVO756, a Novel, Small Molecule Antagonist of MRGPRX2, Potently Inhibits Primary Human Mast Cell Activation

Lorena Blanco – Evommune; Jeegar Patel – Evommune; Jamie Harden – Evommune

Abstract Text: The Mas-Related G-Protein Coupled Receptor X2 (MRGPRX2) contributes to IgE-independent mast cell degranulation and neuroinflammation upon binding various endogenous and exogenous cationic ligands. In humans, the receptor is highly expressed on cutaneous mast cells, which serve as a great tool to study MRGPRX2 biology. Thus, we examined the ability of several MRGPRX2 ligands to activate mast cells derived from human skin by tracking surface expression of degranulation markers, CD63 and CD107a, via flow cytometry. Further, we determined whether MGRPRX2 induced mast cell activation is inhibited by EVO756, a novel, potent, small molecule antagonist of the receptor. Indeed, EVO756 demonstrated potent and concentration-dependent inhibition of primary human skin mast cell degranulation in response to MRGPRX2 agonists. These findings were further confirmed by quantification of tryptase released in the culture supernatant. Therefore, EVO756, which potently inhibits MRGPRX2 mediated mast cell activation, represents a promising therapeutic for the treatment of mast cell driven diseases such as chronic spontaneous urticaria..