Discovery of the First Low Nanomolar Liver Receptor Homolog-1 (LRH-1) Agonist

The liver receptor homolog-1 (LRH-1, NR5A2), a member of the nuclear receptor superfamily, has emerged as a promising drug target for the treatment of diabetes, nonalcoholic fatty liver disease, inflammatory bowel disease, and cancers. However, the discovery of LRH-1 modulators remains a challenge since the large and hydrophobic ligand binding pocket of LRH-1 has been difficult to target. This Viewpoint discusses the recent discovery, published in this journal, that the first low nanomolar LRH-1 agonist was identified through structure-guided design. The agonist binds deep inside the LRH-1 ligand binding pocket by a novel mechanism of action.