Abstract
Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / immunology
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Arthritis, Experimental / metabolism
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Arthritis, Rheumatoid / drug therapy*
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism
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Autoantibodies / immunology
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Autoantibodies / metabolism
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B-Lymphocytes / drug effects*
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Benzamides / chemistry
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Benzamides / pharmacology
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Benzamides / therapeutic use*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Mice
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Myeloid Cells / drug effects*
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / pharmacology
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Protein-Tyrosine Kinases / therapeutic use
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Autoantibodies
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Benzamides
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Bridged Bicyclo Compounds, Heterocyclic
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CGI 1746
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Interleukin-1beta
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Interleukin-6
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse
Associated data
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PDB/3OCS
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PDB/3OCT
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PDB/3P08
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PubChem-Substance/99453934
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PubChem-Substance/99453935
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PubChem-Substance/99453936
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PubChem-Substance/99453937
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PubChem-Substance/99453938
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PubChem-Substance/99453939
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PubChem-Substance/99453940