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

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

doi:10.1021/acs.jmedchem.0c00012

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

Journal Article · Wed Mar 11 00:00:00 EDT 2020 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.0c00012· OSTI ID:1839765

Bartolini, Desirée ^[1]; De Franco, Francesca ^[2]; Torquato, Pierangelo ^[1]; Marinelli, Rita ^[1];

^[1]; Ronchetti, Riccardo ^[1]; Schon, Arne ^[3];

^[1]; De Luca, Antonella ^[1]; Bellezza, Guido ^[1]; Ferri, Ivana ^[1]; Sidoni, Angelo ^[1]; Walton, William G. ^[4]; Pellock, Samuel J. ^[4];

^[4]; Mani, Sridhar ^[5]; Pellicciari, Roberto ^[2];

^[1]; Galli, Francesco ^[1]

Univ. of Perugia (italy)
TES Pharma, Perugia (Italy)
Johns Hopkins Univ., Baltimore, MD (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
Albert Einstein College of Medicine, Bronx, NY (United States)

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1839765

Journal Information:: Journal of Medicinal Chemistry, Vol. 63, Issue 7; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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