Development of picomolar liver receptor homolog‐1 agonist

Abstract

Nuclear receptors are ligand‐regulated transcription factors that alter target gene expression in response to the binding of lipophilic signaling molecules. Liver receptor homolog‐1 (LRH‐1) is a nuclear receptor that has shown promise as an anti‐diabetic therapeutic in murine studies and regulates bile acid biosynthesis, steroidogenesis, and glucose homeostasis, making it an attractive target for treating a variety of metabolic diseases. Although phospholipids are the putative endogenous ligands for LRH‐1, they are insoluble, readily remodeled and hydrolyzed, and are only efficacious at very high concentrations, making development of synthetic agonists critical for targeting LRH‐1 in clinical and laboratory contexts. Using structural data that delineated the binding pose of the only class of synthetic agonists known for LRH‐1, we have conducted structure‐activity relationship studies to enhance potency, efficacy, and solubility of small molecules. Specifically, we targeted residues deep within the binding pocket that radically enhance potency, which has led to the first low‐nanomolar LRH‐1 agonist (“6N”). We have also targeted residues contacted by the headgroups of activating phospholipids as a complementary strategy for activation. These modifications resulted in our most efficacious small molecule (“10CA”). To capture the characteristics of both compounds (6N and 10CA), we have synthesized a chimeric small molecule that includes the key moieties of 6N and 10CA responsible for high affinity and efficacy, respectively. Excitingly, this new hybrid compound binds with picomolar affinity, is more efficacious than 10CA, and elicits LRH‐1 target gene expression to a greater degree than either 6N or 10CA alone. The hybrid molecule is our most effective agonist to date, providing a critical tool for both studying LRH‐1 biology and treating a range of metabolic disorders.Support or Funding InformationNIH‐5T32GM008367‐29 (BCDB Training Grant) | NIH‐5R01DK115213‐02 | Emory Catalyst ProgramBinding mode and residue contacts of leading agonists.Figure 1Binding and in‐cell reporter data demonstrating affinity, potency, and efficacy of the hybrid compound relative to our two leading agonists.Figure 2