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Molecular Pharmacology

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Research ArticleArticle

Increasing Human Th17 Differentiation through Activation of Orphan Nuclear Receptor Retinoid Acid-Related Orphan Receptor γ (RORγ) by a Class of Aryl Amide Compounds

Wei Zhang, Jing Zhang, Leiping Fang, Ling Zhou, Shuai Wang, Zhijun Xiang, Yuan Li, Bruce Wisely, Guifeng Zhang, Gang An, Yonghui Wang, Stewart Leung and Zhong Zhong
Molecular Pharmacology October 2012, 82 (4) 583-590; DOI: https://doi.org/10.1124/mol.112.078667
Wei Zhang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Jing Zhang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Leiping Fang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Ling Zhou
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Shuai Wang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Zhijun Xiang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Yuan Li
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Bruce Wisely
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Guifeng Zhang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Gang An
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Yonghui Wang
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Stewart Leung
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Zhong Zhong
Discovery Technology (W.Z., J.Z., L.F., S.W., Y.L., G.Z., G.A., Z.Z.), Medicinal Chemistry (Y.W.), and Neuroinflammation Discovery Performance Unit (W.Z., J.Z., L.F., L.Z., Z.X., Y.W., S.L.), GlaxoSmithKline R&D Center, Shanghai, China; and Biological Reagents and Assay Development, Platform Technology Science, GlaxoSmithKline, Research Triangle Park, North Carolina (B.W.)
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Abstract

In a screen for small-molecule inhibitors of retinoid acid-related orphan receptor γ (RORγ), we fortuitously discovered that a class of aryl amide compounds behaved as functional activators of the interleukin 17 (IL-17) reporter in Jurkat cells. Three of these compounds were selected for further analysis and found to activate the IL-17 reporter with potencies of ∼0.1 μM measured by EC50. These compounds were shown to directly bind to RORγ by circular dichroism-based thermal stability experiments. Furthermore, they can enhance an in vitro Th17 differentiation process in human primary T cells. As RORγ remains an orphan nuclear receptor, discovery of these aryl amide compounds as functional agonists will now provide pharmacological tools for us to dissect functions of RORγ and facilitate drug discovery efforts for immune-modulating therapies.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

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

    http://dx.doi.org/10.1124/mol.112.078667.

  • ABBREVIATIONS:

    ROR
    retinoid acid-related orphan receptor
    LBD
    ligand binding domain
    Th17
    T-helper 17
    IL
    interleukin
    CNS
    conserved noncoding sequence
    PBS
    phosphate-buffered saline
    SRC
    steroid receptor coactivator
    FRET
    fluorescence resonance energy transfer
    TR
    time-resolved
    APC
    allophycocyanin
    DMSO
    dimethyl sulfoxide
    T0901317
    N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide
    SR1078
    N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(trifluoromethyl)benzamide
    inhibitor Y
    N-(5-benzoyl-4-phenylthiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide
    compound 1b
    N-(4,6-dimethylbenzo[d]thiazol-2-yl)-3-methylthiophene-2-carboxamide
    compound 1c
    N-(2-(4-ethylphenyl)-2H-benzo[d][1,2,3]triazol-5-yl)propionamide
    CD
    circular dichroism
    h
    human
    ELISA
    enzyme-linked immunosorbent assay
    inh%
    percentage of inhibition.

  • Received March 7, 2012.
  • Accepted June 14, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

RORγ Activation by Potent Small-Molecule Compounds

Wei Zhang, Jing Zhang, Leiping Fang, Ling Zhou, Shuai Wang, Zhijun Xiang, Yuan Li, Bruce Wisely, Guifeng Zhang, Gang An, Yonghui Wang, Stewart Leung and Zhong Zhong
Molecular Pharmacology October 1, 2012, 82 (4) 583-590; DOI: https://doi.org/10.1124/mol.112.078667

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Research ArticleArticle

RORγ Activation by Potent Small-Molecule Compounds

Wei Zhang, Jing Zhang, Leiping Fang, Ling Zhou, Shuai Wang, Zhijun Xiang, Yuan Li, Bruce Wisely, Guifeng Zhang, Gang An, Yonghui Wang, Stewart Leung and Zhong Zhong
Molecular Pharmacology October 1, 2012, 82 (4) 583-590; DOI: https://doi.org/10.1124/mol.112.078667
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