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Molecular Pharmacology

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Research ArticleArticle

The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

Naresh Kumar, Laura A. Solt, Juliana J. Conkright, Yongjun Wang, Monica A. Istrate, Scott A. Busby, Ruben D. Garcia-Ordonez, Thomas P. Burris and Patrick R. Griffin
Molecular Pharmacology February 2010, 77 (2) 228-236; DOI: https://doi.org/10.1124/mol.109.060905
Naresh Kumar
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Laura A. Solt
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Juliana J. Conkright
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Yongjun Wang
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Monica A. Istrate
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Scott A. Busby
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Ruben D. Garcia-Ordonez
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Thomas P. Burris
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Patrick R. Griffin
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Abstract

Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grant U54-MH074404]; the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM084041]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Disease [Grant R01-DK080201]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS066417].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.060905.

  • ABBREVIATIONS:

    NR
    nuclear receptor
    ROR
    retinoic acid receptor-related orphan receptor
    ChIP
    chromatin immunoprecipitation
    SRC2
    steroid receptor coactivator 2
    LXR
    liver X receptor
    G6Pase
    glucose 6-phosphatase
    T0901317
    (2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide
    GW3965
    3-[3-[[[2-chloro-3-(trifluoromethyl)phenyl]methyl](2,2 -diphenylethyl) amino]propoxy]benzeneacetic acid hydrochloride
    siRNA
    small interference RNA
    PCR
    polymerase chain reaction
    DBD
    DNA binding domain
    LBD
    ligand binding domain
    HEK
    human embryonic kidney
    DMSO
    dimethyl sulfoxide
    RORE
    retinoic acid receptor-related orphan receptor response element
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    IL
    interleukin.

  • Received September 10, 2009.
  • Accepted November 3, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

Naresh Kumar, Laura A. Solt, Juliana J. Conkright, Yongjun Wang, Monica A. Istrate, Scott A. Busby, Ruben D. Garcia-Ordonez, Thomas P. Burris and Patrick R. Griffin
Molecular Pharmacology February 1, 2010, 77 (2) 228-236; DOI: https://doi.org/10.1124/mol.109.060905

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Research ArticleArticle

The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

Naresh Kumar, Laura A. Solt, Juliana J. Conkright, Yongjun Wang, Monica A. Istrate, Scott A. Busby, Ruben D. Garcia-Ordonez, Thomas P. Burris and Patrick R. Griffin
Molecular Pharmacology February 1, 2010, 77 (2) 228-236; DOI: https://doi.org/10.1124/mol.109.060905
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