Efficient Discovery of Selective Small Molecule Agonists of Estrogen-Related Receptor gamma using Combinatorial Approach

Abstract

With the goal of discovering a selective agonist of estrogen-related receptor gamma (ERR gamma) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERR gamma agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERR gamma. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies oil the receptor cavities of ERR gamma LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERR gamma transcriptional activity with selectivity over ERR alpha/beta enables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERR gamma agonist, E6, with excellent selectivity over ERR alpha/beta.