- Mays, Suzanne G;
- Flynn, Autumn R;
- Cornelison, Jeffery L;
- Okafor, C Denise;
- Wang, Hongtao;
- Wang, Guohui;
- Huang, Xiangsheng;
- Donaldson, Heather N;
- Millings, Elizabeth J;
- Polavarapu, Rohini;
- Moore, David D;
- Calvert, John W;
- Jui, Nathan T;
- Ortlund, Eric A
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.