2. Academic Validation
  3. Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

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

  • J Med Chem. 2020 Apr 9;63(7):3701-3712. doi: 10.1021/acs.jmedchem.0c00012.
Desirée Bartolini 1,  Francesca De Franco 2,  Pierangelo Torquato 1,  Rita Marinelli 1,  Bruno Cerra 1,  Riccardo Ronchetti 1,  Arne Schon 3,  Francesca Fallarino 4,  Antonella De Luca 5,  Guido Bellezza 5,  Ivana Ferri 5,  Angelo Sidoni 5,  William G Walton 6,  Samuel J Pellock 6,  Matthew R Redinbo 6,  Sridhar Mani 7,  Roberto Pellicciari 2,  Antimo Gioiello 1,  Francesco Galli 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, Perugia 06122, Italy.
  • 2 Taverne di Corciano, TES Pharma, Perugia 06073, Italy.
  • 3 The Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, United States.
  • 4 Department of Experimental Medicine, University of Perugia, Perugia 06129, Italy.
  • 5 Section of Anatomic Pathology and Histology, Department of Experimental Medicine, University of Perugia, Perugia 06129, Italy.
  • 6 Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 7 The Departments of Biochemistry, Medicine, Genetics, and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
PMID: 32160459 DOI: 10.1021/acs.jmedchem.0c00012
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.

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