Innovating Your Drug Discovery

The Mast Cell Receptor MRGX2 and Drug-Induced Anaphylaxis

In a recent webinar Dr. Andrew J Brown, Research Fellow, GSK, presented a compelling narrative on the pharmacological characterization of the MRGX2 gene. Dr. Brown emphasized the receptor’s importance as a liability target in drug development and proposed a role for the orphan in immune function.

Dr. Brown, who has a long and well-respected track record in studying Orphan GPCR’s to develop novel therapeutics, has been keenly interested in the MRGX2 receptor and its intriguing history.  Despite significant efforts, the exact function and role for the MRGX2 receptor have been elusive, but intriguing given its mast cell expression profile.  However, Dr. Brown’s research into the receptor assigns it an important physiological role and its promiscuous pharmacology should be of critical interest to drug discovery and development teams.

The catalyst for much of the recent focus on the receptor was a 2014 Nature Paper from a group led by Dong at Johns Hopkins.  Nature (2014) 519, 237–241; McNeil et al.  This paper was the first to elucidate a physiological role for the receptor.  Previously, studies with the human receptor had revealed surrogate ligand pairings but had not been able to link the receptor to its biological function, primarily due to the lack of understanding of the genetics of ortholog receptors.  In this paper, the group focused on the rodent (mouse) ortholog gene, recapitulated the same pharmacology observed with the human MRGX2, and used knockout studies to link the receptor to mast cell function and anaphylaxis.

Using bioinformatics, Dr. Brown at GSK identified and studied a series of orthologs used to support drug development, with the receptor’s link to drug induced anaphylaxis becoming the focus.  In-house recombinant expression studies and compound profiling, done using DiscoverX b-arrestin recruitment and calcium signaling assays, provided a rigorous characterization of compound pharmacology.

When looking back on a series of drug discovery programs where anaphylaxis in animals had curtailed development, the molecules were shown to exhibit MRGX2 pharmacology at the corresponding ortholog gene.  Notably, these programs were studying diverse chemotypes.  Further analysis and insight correlate diverse pharmacology to a molecule’s net charge or pH rather than any specific peptide sequence or structural features.  Indeed, the promiscuity of the MRGX2 receptor supports Dr. Brown’s hypothesis that it functions as a sensor for exogenous and potentially harmful (viral) peptides, invoking a mast cell host response.  This is analogous to the function of the FPR1 receptor, a promiscuous receptor without an established cognate ligand, that senses patterns of bacterial peptides.

The promiscuity of the pharmacology and associated physiology of MRGX2 has led GSK to include the receptor in its safety panel for the early identification of potential compound liabilities.  With profiling services and assays available as cell lines, DiscoverX is ready to support your studies of the MRGX2 receptor.

View Dr. Brown’s webinar

Application Note: Ligand Characterization of Mas-Related GPCR-X2 via Cell-Based Assays: Assessing the Regulation of Mast Cell Function and Implications in Safety Pharmacology