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.