1. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.
- Author
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Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE, Diehl L, Ferrando R, Gallion SL, Giannetti AM, Gribling P, Hurez V, Hymowitz SG, Jones R, Kropf JE, Lee WP, Maciejewski PM, Mitchell SA, Rong H, Staker BL, Whitney JA, Yeh S, Young WB, Yu C, Zhang J, Reif K, and Currie KS
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Animals, Arthritis, Experimental immunology, Arthritis, Experimental metabolism, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, Autoantibodies immunology, Autoantibodies metabolism, B-Lymphocytes immunology, B-Lymphocytes metabolism, Benzamides chemistry, Benzamides pharmacology, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Proliferation drug effects, Enzyme Activation drug effects, Interleukin-1beta immunology, Interleukin-1beta metabolism, Interleukin-6 immunology, Interleukin-6 metabolism, Mice, Myeloid Cells immunology, Myeloid Cells metabolism, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases pharmacology, Protein-Tyrosine Kinases therapeutic use, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Arthritis, Experimental drug therapy, Arthritis, Rheumatoid drug therapy, B-Lymphocytes drug effects, Benzamides therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Myeloid Cells drug effects, Protein Kinase Inhibitors therapeutic use
- 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.
- Published
- 2011
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