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Molecular Pharmacology

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Research ArticleArticle

TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules

Naoko Matsunaga, Noboru Tsuchimori, Tatsumi Matsumoto and Masayuki Ii
Molecular Pharmacology January 2011, 79 (1) 34-41; DOI: https://doi.org/10.1124/mol.110.068064
Naoko Matsunaga
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Noboru Tsuchimori
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Tatsumi Matsumoto
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Masayuki Ii
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Abstract

TAK-242 (resatorvid), a small-molecule–specific inhibitor of Toll-like receptor (TLR) 4 signaling, inhibits the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4. Cys747 in TLR4 has been identified previously as the binding site of TAK-242. However, the mechanism by which TAK-242 inhibits TLR4 signaling after binding to TLR4 remains unknown. The present study demonstrated, using coimmunoprecipitation, that TAK-242 interferes with protein-protein interactions between TLR4 and its adaptor molecules. Among 10 different human TLRs, TAK-242 selectively bound to TLR4. The time course of the inhibitory effect of TAK-242 on inflammatory mediator production corresponded to that of the binding of TAK-242 to TLR4. TAK-242 inhibited the association of TLR4 with Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) or Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β-related adaptor molecule (TRAM) in human embryonic kidney (HEK) 293 cells overexpressing TLR4, MD-2, and TIRAP or TRAM, respectively. TAK-242 inhibited the TIRAP-mediated activation of nuclear factor κB (NF-κB) and the TRAM-mediated activation of NF-κB and interferon-sensitive response element in HEK293 cells stably expressing TLR4, MD-2, and CD14. The activation of endogenous interleukin-1 receptor-associated kinase in RAW264.7 cells was also inhibited by TAK-242 treatment. These findings suggest that TAK-242 binds selectively to TLR4 and subsequently disrupts the interaction of TLR4 with adaptor molecules, thereby inhibiting TLR4 signal transduction and its downstream signaling events. This work proposes a novel paradigm of a small molecule capable of disrupting protein-protein interactions.

Footnotes

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

    doi:10.1124/mol.110.068064.

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

  • ABBREVIATIONS:

    TLR
    Toll-like receptor
    LPS
    lipopolysaccharide
    IL
    interleukin
    IFN
    interferon
    TNF
    tumor necrosis factor
    TIR
    Toll/interleukin-1 receptor
    MyD88
    myeloid differentiation primary response gene 88
    TIRAP
    Toll/interleukin-1 receptor domain-containing adaptor protein
    TRIF
    Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β
    TRAM
    Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β-related adaptor molecule
    IRAK
    interleukin-1 receptor-associated kinase
    HEK
    human embryonic kidney
    TAK-242 (resatorvid)
    ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate
    NF-κB
    nuclear factor-κB
    ISRE
    interferon-sensitive response element
    Ab
    antibody
    mAb
    monoclonal antibody
    PAGE
    polyacrylamide gel electrophoresis
    HA
    hemagglutinin
    FCS
    fetal calf serum
    DMEM
    Dulbecco's modified Eagle's medium
    TK
    thymidine kinase
    BAY 11-7082
    3-[(4-methylphenyl)sulfonyl]-(2E)-propenenitrile
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    SP600125
    1,9-pyrazoloanthrone.

  • Received August 9, 2010.
  • Accepted September 29, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (1)
Molecular Pharmacology
Vol. 79, Issue 1
1 Jan 2011
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Research ArticleArticle

TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules

Naoko Matsunaga, Noboru Tsuchimori, Tatsumi Matsumoto and Masayuki Ii
Molecular Pharmacology January 1, 2011, 79 (1) 34-41; DOI: https://doi.org/10.1124/mol.110.068064

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Research ArticleArticle

TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules

Naoko Matsunaga, Noboru Tsuchimori, Tatsumi Matsumoto and Masayuki Ii
Molecular Pharmacology January 1, 2011, 79 (1) 34-41; DOI: https://doi.org/10.1124/mol.110.068064
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