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Research ArticleArticle

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

Prajakta S. Palkar, Michael G. Borland, Simone Naruhn, Christina H. Ferry, Christina Lee, Ugir H. Sk, Arun K. Sharma, Shantu Amin, Iain A. Murray, Cherie R. Anderson, Gary H. Perdew, Frank J. Gonzalez, Rolf Müller and Jeffrey M. Peters
Molecular Pharmacology September 2010, 78 (3) 419-430; DOI: https://doi.org/10.1124/mol.110.065508
Prajakta S. Palkar
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Michael G. Borland
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Simone Naruhn
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Christina H. Ferry
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Christina Lee
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Ugir H. Sk
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Arun K. Sharma
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Shantu Amin
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Iain A. Murray
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Cherie R. Anderson
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Gary H. Perdew
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Frank J. Gonzalez
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Rolf Müller
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Jeffrey M. Peters
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Abstract

The availability of high-affinity agonists for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has led to significant advances in our understanding of the functional role of PPARβ/δ. In this study, a new PPARβ/δ antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Pparβ/δ-null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPARβ/δ on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPARβ/δ activity and weak antagonism and agonism of PPARγ activity but no effect on PPARα activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPARβ/δ and PPARγ coregulator peptides in response to ligand activation, consistent with reporter assays. In vivo and in vitro analysis indicates that the efficacy of GSK3787 to modulate PPARγ activity is markedly lower than the efficacy of GSK3787 to act as a PPARβ/δ antagonist. GSK3787 antagonized GW0742-induced expression of Angptl4 in mouse fibroblasts, mouse keratinocytes, and human cancer cell lines. Cell proliferation was unchanged in response to either GW0742 or GSK3787 in human cancer cell lines. Results from these studies demonstrate that GSK3787 can antagonize PPARβ/δ in vivo, thus providing a new strategy to delineate the functional role of a receptor with great potential as a therapeutic target for the treatment and prevention of disease.

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 [Grants CA124533, CA126826, CA141029]; the Deutsche Forschungsgemeinschaft [Grant SFB-TR17/A3]; and in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute.

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

    doi:10.1124/mol.110.065508.

  • ABBREVIATIONS:

    PPAR
    peroxisome proliferator-activated receptor
    Adrp
    adipocyte differentiation-related protein
    ANOVA
    analysis of variance
    Angptl4
    angiopoietin-like protein 4
    ChIP
    chromatin immunoprecipitation
    DMSO
    dimethyl sulfoxide
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    PPRE
    peroxisome proliferator response element
    PCR
    polymerase chain reaction
    TR-FRET
    time-resolved fluorescence resonance energy transfer
    TRAP220/DRIP-1
    thyroid hormone receptor-associated protein 220/vitamin D receptor interacting protein-1
    SMRT-ID2
    silencing mediator for retinoid and thyroid hormone receptors interaction domain 2
    NCoR-ID2
    nuclear receptor corepressor interaction domain 2
    AcH4
    acetylated histone H4
    LBD
    ligand binding domain
    qPCR
    quantitative real-time polymerase chain reaction
    PDK4
    pyruvate dehydrogenase kinase 4
    CPT1a
    carnitine palmitoyl transferase 1a
    GST
    glutathione transferase
    GSK3787
    4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide
    GW0742
    4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid
    GW501516
    (2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl) phenyl)-5-thiazolyl)methyl)thio)phenoxy)-acetic acid
    GSK0660
    3-[[[2-methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester
    GW1929
    N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrochloride
    GW7647
    2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid.

  • Received April 9, 2010.
  • Accepted June 1, 2010.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

Prajakta S. Palkar, Michael G. Borland, Simone Naruhn, Christina H. Ferry, Christina Lee, Ugir H. Sk, Arun K. Sharma, Shantu Amin, Iain A. Murray, Cherie R. Anderson, Gary H. Perdew, Frank J. Gonzalez, Rolf Müller and Jeffrey M. Peters
Molecular Pharmacology September 1, 2010, 78 (3) 419-430; DOI: https://doi.org/10.1124/mol.110.065508

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Research ArticleArticle

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

Prajakta S. Palkar, Michael G. Borland, Simone Naruhn, Christina H. Ferry, Christina Lee, Ugir H. Sk, Arun K. Sharma, Shantu Amin, Iain A. Murray, Cherie R. Anderson, Gary H. Perdew, Frank J. Gonzalez, Rolf Müller and Jeffrey M. Peters
Molecular Pharmacology September 1, 2010, 78 (3) 419-430; DOI: https://doi.org/10.1124/mol.110.065508
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