Steroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands.
View Article and Find Full Text PDFLiver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies.
View Article and Find Full Text PDFPhospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery.
View Article and Find Full Text PDFLRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded.
View Article and Find Full Text PDFAs regulators of steroidogenesis, development, and metabolism, the nuclear receptor 5A (NR5A) subfamily members steroidogenic factor 1 (SF-1) and liver receptor homologue 1 (LRH-1) are important pharmacological targets for cancers and metabolic diseases. Evaluation of small molecule modulators and candidate endogenous ligands for these orphan receptors has been hindered by the lack of accessible, robust direct-binding assays. Here, we leverage the potency of our new NR5A agonist (6N) to create a high-affinity probe for fluorescence polarization competition assays by conjugating 6N to fluorescein (FAM).
View Article and Find Full Text PDFAs a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, liver receptor homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly discovered polar interaction to lock agonists in a consistent orientation.
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