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Research ArticleArticle

In Vivo and In Vitro Characterization of a First-in-Class Novel Azole Analog That Targets Pregnane X Receptor Activation

Madhukumar Venkatesh, Hongwei Wang, Julie Cayer, Melissa Leroux, Dany Salvail, Bhaskar Das, Jay E. Wrobel and Sridhar Mani
Molecular Pharmacology July 2011, 80 (1) 124-135; DOI: https://doi.org/10.1124/mol.111.071787
Madhukumar Venkatesh
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Hongwei Wang
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Julie Cayer
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Melissa Leroux
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Dany Salvail
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Bhaskar Das
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Jay E. Wrobel
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Sridhar Mani
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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

  • ↵Embedded Image 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.

  • 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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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

In Vivo and In Vitro Characterization of a First-in-Class Novel Azole Analog That Targets Pregnane X Receptor Activation

Madhukumar Venkatesh, Hongwei Wang, Julie Cayer, Melissa Leroux, Dany Salvail, Bhaskar Das, Jay E. Wrobel and Sridhar Mani
Molecular Pharmacology July 1, 2011, 80 (1) 124-135; DOI: https://doi.org/10.1124/mol.111.071787

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Research ArticleArticle

In Vivo and In Vitro Characterization of a First-in-Class Novel Azole Analog That Targets Pregnane X Receptor Activation

Madhukumar Venkatesh, Hongwei Wang, Julie Cayer, Melissa Leroux, Dany Salvail, Bhaskar Das, Jay E. Wrobel and Sridhar Mani
Molecular Pharmacology July 1, 2011, 80 (1) 124-135; DOI: https://doi.org/10.1124/mol.111.071787
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