Differential modulation of nuclear receptor LRH-1 through targeting buried and surface regions of the binding pocket

Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unusually large ligand binding pocket but generating synthetic modulators has been challenging. Leveraging a hexahydropentalene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pocket. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells. Overall design: Examination of compound-mediated effects on transcriptome of HepG2 cells.