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Research ArticleArticle

Glucocorticoid Receptor Antagonism by Cyproterone Acetate and RU486

Christian Honer, Kiyean Nam, Cynthia Fink, Paul Marshall, Gary Ksander, Ricardo E. Chatelain, Wendy Cornell, Ronald Steele, Robert Schweitzer and Christoph Schumacher
Molecular Pharmacology May 2003, 63 (5) 1012-1020; DOI: https://doi.org/10.1124/mol.63.5.1012
Christian Honer
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Kiyean Nam
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Cynthia Fink
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Paul Marshall
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Gary Ksander
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Ricardo E. Chatelain
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Wendy Cornell
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Ronald Steele
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Robert Schweitzer
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Christoph Schumacher
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Abstract

The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (Kd, 15–70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (Ki, 10–30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasone-induced GR transactivation and NFκB transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11β that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.

Footnotes

  • This work was supported by the University of Medicine and Dentistry of New Jersey/Novartis Predoctoral Fellowship Program.

  • Abbreviations:
    GR
    glucocorticoid receptor
    GRE
    glucocorticoid response element
    NF-κB
    nuclear factor κB
    AP-1
    activator protein 1
    LBD
    ligand-binding domain
    AF-2
    activation function 2
    RU486
    mifepristone
    PR
    progesterone receptor
    DMSO
    dimethyl sulfoxide
    DTT
    dithiothreitol
    FP
    fluorescence polarization
    Fluormone-GS1
    fluorescent glucosteroid
    PL
    progesterone ligand
    IL
    interleukin
    TAT
    tyrosine aminotransferase
    THC
    (R,R)-5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol
    • Received October 2, 2002.
    • Accepted February 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Glucocorticoid Receptor Antagonism by Cyproterone Acetate and RU486

Christian Honer, Kiyean Nam, Cynthia Fink, Paul Marshall, Gary Ksander, Ricardo E. Chatelain, Wendy Cornell, Ronald Steele, Robert Schweitzer and Christoph Schumacher
Molecular Pharmacology May 1, 2003, 63 (5) 1012-1020; DOI: https://doi.org/10.1124/mol.63.5.1012

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Research ArticleArticle

Glucocorticoid Receptor Antagonism by Cyproterone Acetate and RU486

Christian Honer, Kiyean Nam, Cynthia Fink, Paul Marshall, Gary Ksander, Ricardo E. Chatelain, Wendy Cornell, Ronald Steele, Robert Schweitzer and Christoph Schumacher
Molecular Pharmacology May 1, 2003, 63 (5) 1012-1020; DOI: https://doi.org/10.1124/mol.63.5.1012
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