title: In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation.
abstract: The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here we report the development and characterization of a first-in-class novel azole analog [1-(4-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone (FLB-12)] that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., liver X receptor, farnesoid X receptor, estrogen receptor α, peroxisome proliferator-activated receptor γ, and mouse constitutive androstane receptor). We investigated the toxicity and PXR antagonist effect of FLB-12 in vivo. Compared with ketoconazole, a prototypical PXR antagonist, FLB-12 is significantly less toxic to hepatocytes. FLB-12 significantly inhibits the PXR-activated loss of righting reflex to 2,2,2-tribromoethanol (Avertin) in vivo, abrogates PXR-mediated resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in colon cancer cells in vitro, and attenuates PXR-mediated acetaminophen hepatotoxicity in vivo. Thus, relatively selective targeting of PXR by antagonists is feasible and warrants further investigation. This class of agents is suitable for development as chemical probes of PXR function as well as potential PXR-directed therapeutics.
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Madhukumar
authors.initials: M
authors.lastname: Venkatesh
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Julie
authors.initials: J
authors.lastname: Cayer
authors.forename: Melissa
authors.initials: M
authors.lastname: Leroux
authors.forename: Dany
authors.initials: D
authors.lastname: Salvail
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Das
authors.forename: Jay E
authors.initials: JE
authors.lastname: Wrobel
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D001393:Azoles; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid