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Research ArticleInflammation, Immunopharmacology, and Asthma

RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents

Daigen Xu, Yong Kim, Jennifer Postelnek, Minh Diem Vu, Dong-Qing Hu, Cheng Liao, Mike Bradshaw, Jonathan Hsu, Jun Zhang, Achal Pashine, Dinesh Srinivasan, John Woods, Anita Levin, Alison O'Mahony, Timothy D. Owens, Yan Lou, Ronald J. Hill, Satwant Narula, Julie DeMartino and Jay S. Fine
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 90-103; DOI: https://doi.org/10.1124/jpet.111.187740
Daigen Xu
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Yong Kim
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Jennifer Postelnek
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Minh Diem Vu
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Dong-Qing Hu
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Cheng Liao
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Mike Bradshaw
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Jonathan Hsu
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Jun Zhang
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Achal Pashine
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Dinesh Srinivasan
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John Woods
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Anita Levin
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Alison O'Mahony
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Timothy D. Owens
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Yan Lou
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Ronald J. Hill
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Satwant Narula
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Julie DeMartino
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Jay S. Fine
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Abstract

Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (RN486), in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fcε receptor cross-linking-induced degranulation in mast cells (IC50 = 2.9 nM), Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC50 = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC50 = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.187740.

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

  • ABBREVIATIONS:

    RA
    rheumatoid arthritis
    AIA
    adjuvant-induced arthritis
    BCR
    B cell antigen receptor
    Btk
    Bruton's tyrosine kinase
    CAIA
    collagen antibody-induced arthritis
    CIA
    collagen-induced arthritis
    CRP
    C reactive protein
    CSF1R
    colony-stimulating factor 1 receptor
    CT
    computer tomography
    DAP12
    DNAx adaptor protein of 12 kDa
    Dex
    dexamethasone
    DMSO
    dimethyl sulfoxide
    Eu
    europium
    FACS
    fluorescence-activated cell sorter
    FcR
    Fc receptor
    FRET
    fluorescence resonance energy transfer
    HuVEC
    human venular endothelial cell
    IFN
    interferon
    IL
    interleukin
    ITAM
    immunoreceptor tyrosine activation motif
    JAK
    Janus kinase
    LPS
    lipopolysaccharide
    MCP
    monocyte chemoattractant protein
    MTX
    methotrexate
    NP
    4-hydroxy-3-nitrophenylacetyl
    OVA
    ovalbumin
    PBMC
    peripheral blood mononuclear cell
    PCA
    passive cutaneous anaphylaxis
    PLCγ2
    phospholipase Cγ2
    RANKL
    receptor activator of nuclear factor-κB ligand
    rPAR
    reverse passive Arthurs' reaction
    SLK
    Ste20-like kinase
    Syk
    spleen tyrosine kinase
    TCR
    T cell receptor
    TNF
    tumor necrosis factor
    RN486
    6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one
    PCI-32765
    1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
    CGI1746
    N-[3-[4,5-dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide
    GDC-0834
    R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
    A23187
    5-(methylamino)-2-({(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl}methyl)-1,3-benzoxazole-4-carboxylic acid.

  • Received September 9, 2011.
  • Accepted December 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

Btk Inhibitors for Rheumatoid Arthritis

Daigen Xu, Yong Kim, Jennifer Postelnek, Minh Diem Vu, Dong-Qing Hu, Cheng Liao, Mike Bradshaw, Jonathan Hsu, Jun Zhang, Achal Pashine, Dinesh Srinivasan, John Woods, Anita Levin, Alison O'Mahony, Timothy D. Owens, Yan Lou, Ronald J. Hill, Satwant Narula, Julie DeMartino and Jay S. Fine
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 90-103; DOI: https://doi.org/10.1124/jpet.111.187740

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Research ArticleInflammation, Immunopharmacology, and Asthma

Btk Inhibitors for Rheumatoid Arthritis

Daigen Xu, Yong Kim, Jennifer Postelnek, Minh Diem Vu, Dong-Qing Hu, Cheng Liao, Mike Bradshaw, Jonathan Hsu, Jun Zhang, Achal Pashine, Dinesh Srinivasan, John Woods, Anita Levin, Alison O'Mahony, Timothy D. Owens, Yan Lou, Ronald J. Hill, Satwant Narula, Julie DeMartino and Jay S. Fine
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 90-103; DOI: https://doi.org/10.1124/jpet.111.187740
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