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.
Footnotes
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.This work was supported by the National Institutes of Health National Cancer Institute [Grant CA12723101]; the Damon Runyon Foundation [Clinical Investigator Award CI 1502]; and Phase I Program, Albert Einstein College of Medicine.
The current ketoconazole analogs are under patent protection (WO/2009/110955), by Albert Einstein College of Medicine, Bronx, NY 10461.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.071787.
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ABBREVIATIONS:
- PXR
- pregnane X receptor
- ET-743
- trabectedin
- A-792611
- methyl 1-(5-(2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate
- SAA
- serum amyloid A
- PCN
- pregnenolone-16α-carbonitrile
- LBD
- ligand binding domain
- T0901317
- N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]benzenesulfonamide
- Rif
- rifampicin
- h
- human
- m
- mouse
- mCAR
- mouse constitutive androstane receptor
- LXR
- liver X receptor
- FXR
- farnesoid X receptor
- ERα
- estrogen receptor α
- UGT
- UDP glucuronosyltransferase
- TR-FRET
- time-resolved fluorescence resonance energy transfer
- DMSO
- dimethyl sulfoxide
- PCR
- polymerase chain reaction
- RT
- reverse transcription
- APAP
- acetaminophen
- ALT
- alanine aminotransferase
- KTZ
- ketoconazole
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- AST
- aspartate aminotransferase
- hERG
- human ether-a-go-go-related gene
- ERK
- extracellular signal-regulated kinase
- qPCR
- quantitative polymerase chain reaction
- MDR1
- multidrug resistance protein 1
- PPAR
- peroxisome proliferator-activated receptor
- shRNA
- short hairpin RNA
- LORR
- loss of righting reflex.
- Received February 14, 2011.
- Accepted March 23, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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In Vivo and In Vitro Characterization of a First-in-Class Novel Azole Analog That Targets Pregnane X Receptor Activation
