A First-in-Class Hepatocyte Nuclear Factor 4 Agonist

Hepatocyte nuclear factor 4 (HNF4) is an orphan nuclear receptor implicated, for example, in pancreatic islet gene expression and hepatic regulation of glucose and lipid metabolism. Mutations in the HNF4α gene are responsible for the inheritable maturity-onset diabetes of the young 1 (MODY-1), supporting the therapeutic potential of HNF4 activation in metabolic diseases. However, exploration and validation of HNF4 as a therapeutic target is hindered by the lack of suitable ligands. Here, we report the development of the first high-affinity HNF4 agonists by extension of a fragment screening hit and systematic SAR elucidation. Structural modification allowed tuning of the chemotype for both HNF4 agonism and inverse agonism. X-ray structure analysis demonstrated orthosteric site occupation by the new ligand scaffold mimicking the natural fatty acid ligand binding. The most active descendant displayed low nanomolar HNF4 agonist potency and binding affinity and favorable selectivity, enabling unprecedented studies on HNF4 biology as a chemical tool.