With the goal of discovering a selective agonist of estrogen-related receptor γ (ERRγ) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRγ agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRγ. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRγ LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRγ transcriptional activity with selectivity over ERRα/βenables 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 ERRγ agonist, E6, with excellent selectivity over ERRα/β.
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