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

Desirée Bartolini, Francesca De Franco, Pierangelo Torquato, Rita Marinelli, Bruno Cerra, Riccardo Ronchetti, Arne Schon, Francesca Fallarino, Antonella De Luca, Guido Bellezza, Ivana Ferri, Angelo Sidoni, William G. Walton, Samuel J. Pellock, Matthew R. Redinbo, Sridhar Mani, Roberto Pellicciari, Antimo Gioiello, Francesco Galli

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3701-3712
Number of pages12
JournalJournal of Medicinal Chemistry
Volume63
Issue number7
DOIs
StatePublished - Apr 9 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Bartolini, D., De Franco, F., Torquato, P., Marinelli, R., Cerra, B., Ronchetti, R., Schon, A., Fallarino, F., De Luca, A., Bellezza, G., Ferri, I., Sidoni, A., Walton, W. G., Pellock, S. J., Redinbo, M. R., Mani, S., Pellicciari, R., Gioiello, A., & Galli, F. (2020). Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor. Journal of Medicinal Chemistry, 63(7), 3701-3712. https://doi.org/10.1021/acs.jmedchem.0c00012