TY - JOUR
T1 - Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor
AU - Bartolini, Desirée
AU - De Franco, Francesca
AU - Torquato, Pierangelo
AU - Marinelli, Rita
AU - Cerra, Bruno
AU - Ronchetti, Riccardo
AU - Schon, Arne
AU - Fallarino, Francesca
AU - De Luca, Antonella
AU - Bellezza, Guido
AU - Ferri, Ivana
AU - Sidoni, Angelo
AU - Walton, William G.
AU - Pellock, Samuel J.
AU - Redinbo, Matthew R.
AU - Mani, Sridhar
AU - Pellicciari, Roberto
AU - Gioiello, Antimo
AU - Galli, Francesco
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.0c00012
DO - 10.1021/acs.jmedchem.0c00012
M3 - Article
C2 - 32160459
AN - SCOPUS:85083072939
SN - 0022-2623
VL - 63
SP - 3701
EP - 3712
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -
