Specific Btk inhibition suppresses B cell– and myeloid cell–mediated arthritis
Top Cited Papers
- 28 November 2010
- journal article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 7 (1), 41-50
- https://doi.org/10.1038/nchembio.481
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.Keywords
This publication has 49 references indexed in Scilit:
- Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinasesProtein Science, 2010
- B‐lymphocyte contributions to human autoimmune diseaseImmunological Reviews, 2008
- The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast MaturationPublished by Elsevier BV ,2008
- Therapeutic B cell depletion impairs adaptive and autoreactive CD4+T cell activation in miceProceedings of the National Academy of Sciences of the United States of America, 2007
- A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritisThe Journal of Experimental Medicine, 2007
- Surface‐bound anti–type II collagen–containing immune complexes induce production of tumor necrosis factor α, interleukin‐1β, and interleukin‐8 from peripheral blood monocytes via fcγ receptor IIA: A potential pathophysiologic mechanism for humoral anti–type II collagen immunity in arthritisArthritis & Rheumatism, 2006
- Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profilingImmunological Reviews, 2005
- Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responsesBlood, 2004
- Four Tyrosine Residues in Phospholipase C-γ2, Identified as Btk-dependent Phosphorylation Sites, Are Required for B Cell Antigen Receptor-coupled Calcium SignalingPublished by Elsevier BV ,2001
- Induction of costimulatory molecules B7-1 and B7-2 in murine B cells: The CBAN mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 inductionMolecular Immunology, 1996