EVO756 potently blocks MRGPRX2-mediated mast cell activation as well as MRGPRX2 and IgE-dependent synergistic responses 9241

Abstract Description Mas-related G-protein coupled receptor X2 (MRGPRX2) is a GPCR expressed predominantly by mast cells and has been implicated in playing an important role in diseases such as chronic spontaneous urticaria, atopic dermatitis, asthma and ulcerative colitis. Cationic ligands, either endogenous or exogenous, can activate the receptor and induce IgE-independent mast cell activation, resulting in allergic responses and non-histaminergic itch. Therefore, blocking MRGPRX2 represents a promising therapeutic modality for a plethora of autoimmune conditions. Here we show that EVO756, a novel small molecule antagonist of MRGPRX2, demonstrates potent, concentration dependent inhibition of MRGPRX2 mediated activation in MRGPRX2 transfectants and LAD2 cells. Furthermore, EVO756 inhibits primary human mast cell activity at the transcriptional and proteomic levels, as determined by RNA sequencing and release of disease-causing cytokines, tryptase and surface expression of mast cell granules. We also demonstrate synergism between MRGPRX2-mediated and IgE-dependent primary human mast cell activation, which is inhibited by EVO756. These studies establish EVO756 as a potent inhibitor of MRGPRX2-mediated mast cell activation and therefore, a promising therapeutic for the treatment of mast cell driven diseases. Topic Categories Immune Mechanisms of Human Disease (HUM)