Chemical starting matter for HNF4a ligand discovery and chemogenomics

Hepatocyte nuclear factor 4a (HNF4a) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4a gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure-activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4a activity in a low micromolar range. These compounds demonstrate the druggability of HNF4a and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.