[DOT 2022] Ligand Characterization of Mas-Related GPCR-X2 via Cell-Based Assays: Implications in Safety Liability Tests
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Mast cells are principal players in IgE-, and more recently, non-IgE-mediated anaphylactoid reactions or pseudo-allergic Adverse Drug Reactions (ADR). A wide range of ligands can activate mast cells owing to their multiple receptor expression profiles, and their characterization hence warrants closer study, especially into their safety pharmacological roles. Among the receptor classes, orphan GPCRs have emerged as active proponents in non-immunogenic mast cell activation profiles with possible roles in pseudo-allergic or anaphylactoid reactions (McNeil et al. 2015). A relatively new subfamily of GPCRs associated with the MAS1 oncogene was identified as Mas-Related genes (MRGs) and their receptors, MAS-related GPCRs (MRGPR). One of its members, MrgprX2 encoded by the gene MRGPRX2, has been identified to play a role in the activation of several synthetic small molecules and peptides including U.S. FDA approved drugs. Studies have identified MrgprX2 receptor-mediated agonism to be implicated in causing adverse reactions associated with clinical candidate molecules during their development (Grimes et al. 2019).