Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor with a key role in drug metabolism and disposition. Its activity regulates a number of physiological processes in the liver and intestine, and it is now a validated target for human diseases associated with inflammation and dysregulation of the immune system. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified the naturally-occurring garcinoic acid as a selective and efficient PXR agonist. The properties of garcinoic acid as a specific PXR agonist was demonstrated using different approaches - screening on a panel of nuclear receptors, physical and thermodynamic evaluation of binding affinity, and co-crystallization study. Cytotoxicity assays, transcriptional and functional experiments were carried out in human liver cells, in mouse liver and gut tissue to prove compound activity and target engagement. Taken together, these data support the conclusion that garcinoic acid efficiently activates PXR and may prove to be an amenable lead toward the development of differentially acting PXR regulating compounds.