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

Pregnane X receptor
(PXR) is a master xenobiotic-sensing transcription
factor and a validated target for immune and inflammatory diseases.
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
garcinoic acid as a selective and efficient PXR agonist. The properties
of this natural molecule as a specific PXR agonist were demonstrated
by the screening on a panel of nuclear receptors, the assessment of
the physical and thermodynamic binding affinity, and the determination
of the PXR-garcinoic acid complex crystal structure. Cytotoxicity,
transcriptional, and functional properties were investigated in human
liver cells, and compound activity and target engagement were confirmed
in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid
is a selective natural agonist of PXR and a promising lead compound
toward the development of new PXR-regulating modulators.