MRGPRX2 is a GPCR that has been implicated in a number of mast cell pathologies, including various skin disorders.  As part of a Discovery Partnerships with Academia (DPAc) collaboration, we began working with Professor Xinzhong Dong at Johns Hopkins University to explore the possibility of developing small molecule, orally dosed MRGPRX2 antagonists.  This presentation will highlight the progression of an initial HTS hit to clinical candidate selection, overcoming challenges related to mitochondrial dysfunction.