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ID: ALA4321799
Journal: J Med Chem
Title: Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design.
Authors: Mays SG, Flynn AR, Cornelison JL, Okafor CD, Wang H, Wang G, Huang X, Donaldson HN, Millings EJ, Polavarapu R, Moore DD, Calvert JW, Jui NT, Ortlund EA.
Abstract: As 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. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of IBD, the new agonist increases expression of LRH-1-controlled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.
CiteXplore: 31419141