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Research ArticleDrug Discovery and Translational Medicine

Specific Inhibition of Spleen Tyrosine Kinase Suppresses Leukocyte Immune Function and Inflammation in Animal Models of Rheumatoid Arthritis

Greg Coffey, Francis DeGuzman, Mayuko Inagaki, Yvonne Pak, Suzanne M. Delaney, Dan Ives, Andreas Betz, Zhaozhong J. Jia, Anjali Pandey, Dale Baker, Stanley J. Hollenbach, David R. Phillips and Uma Sinha
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 350-359; DOI: https://doi.org/10.1124/jpet.111.188441
Greg Coffey
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Francis DeGuzman
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Mayuko Inagaki
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Yvonne Pak
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Suzanne M. Delaney
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Dan Ives
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Andreas Betz
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Zhaozhong J. Jia
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Anjali Pandey
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Dale Baker
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Stanley J. Hollenbach
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David R. Phillips
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Uma Sinha
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Abstract

Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1–2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 μM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by ∼67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.188441.

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

  • ABBREVIATIONS:

    Syk
    spleen tyrosine kinase
    pSyk
    phosphorylated Syk
    BCR
    B cell antigen receptor
    CAIA
    collagen antibody-induced arthritis
    CIA
    collagen-induced arthritis
    FRET
    fluorescence resonance energy transfer
    PBS
    phosphate-buffered saline
    PMA
    phorbol 12-myristate 13-acetate
    P505-15
    (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate
    RA
    rheumatoid arthritis
    JAK
    Janus tyrosine kinase
    BLNK
    B cell linker
    pBLNK
    phosphorylated BLNK
    ERK
    extracellular signal-regulated kinase
    pERK
    phosphorylated ERK
    PE
    phycoerythrin
    PerCP
    peridinin-chlorophyll-protein complex
    APC
    allophycocyanin
    BSA
    bovine serum albumin
    TEL
    translocated ETS leukemia
    H&E
    hematoxylin and eosin
    MFI
    mean fluorescence intensity
    CP-690,550
    (3R,4R)-4methyl-3-(methyl-1H-pyrrolo[2,3-d]pyrimidine-4-ylamino]-ß-oxo-1-piperidinepropanenitrile.

  • Received September 26, 2011.
  • Accepted October 25, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleDrug Discovery and Translational Medicine

Specific Inhibition of Syk Suppresses Inflammation

Greg Coffey, Francis DeGuzman, Mayuko Inagaki, Yvonne Pak, Suzanne M. Delaney, Dan Ives, Andreas Betz, Zhaozhong J. Jia, Anjali Pandey, Dale Baker, Stanley J. Hollenbach, David R. Phillips and Uma Sinha
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 350-359; DOI: https://doi.org/10.1124/jpet.111.188441

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Research ArticleDrug Discovery and Translational Medicine

Specific Inhibition of Syk Suppresses Inflammation

Greg Coffey, Francis DeGuzman, Mayuko Inagaki, Yvonne Pak, Suzanne M. Delaney, Dan Ives, Andreas Betz, Zhaozhong J. Jia, Anjali Pandey, Dale Baker, Stanley J. Hollenbach, David R. Phillips and Uma Sinha
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 350-359; DOI: https://doi.org/10.1124/jpet.111.188441
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