Fatty Acid Mimetic Fragments as Liver Receptor Homologue-1 Modulators

The phospholipid-sensing transcription factor liver receptor homologue-1 (LRH-1) is mainly found in the liver, intestine, and pancreas where it participates in the transcriptional regulation of genes involved in cholesterol and glucose metabolism, inflammation, and endoplasmic reticulum stress. It holds promise as a target in metabolic disease and hepatic/intestinal inflammation treatment, and preliminary evidence suggests potential of LRH-1 modulation for contraception, but LRH-1 modulators are very rare. Based on phospholipid binding to LRH-1, we hypothesized potential for fatty acid mimetics as LRH-1 modulators and discovered new ligand chemotypes by focused fragment screening. Preliminary SAR elucidation, orthogonal activity validation, and target engagement studies highlighted two fragment-like leads for LRH-1 agonist development.