FLG249 Exhibits FXR Antagonist Activity by Inducing Dissociation of Both Corepressors and Coactivators from FXR

The farnesoid X receptor (FXR), a nuclear receptor activated by endogenous bile acids, regulates not only bile acid synthesis but also lipid and carbohydrate metabolism. Therefore, FXR ligands, including FXR antagonists, show potential as therapeutic agents for various metabolic diseases. However, the mechanism by which FXR antagonists influence FXR activity is unclear. We previously synthesized an FXR antagonist, FLG249, which reduced the expression of several FXR target genes in the mouse ileum when orally administered and improved lipid metabolism in the liver and ileum of high-fat diet-induced obese mice. In the present study, we aimed to characterize the mechanism by which FLG249 inhibits the interaction of FXR with its coactivators and corepressors. The LanthaScreen^TM time-resolved fluorescence energy transfer assay and two-hybrid assay were used to evaluate the effect of FLG249 on FXR. We found that, upon binding, FLG249 reduced the interaction of FXR with both coactivators and corepressors. This result suggests that the mechanism of FLG249 as a nuclear receptor modulator is distinct from that of previously reported neutral antagonists and inverse agonists of nuclear receptors.