2. Academic Validation
  3. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

  • Nat Chem Biol. 2011 Jan;7(1):41-50. doi: 10.1038/nchembio.481.
Julie A Di Paolo 1,  Tao Huang,  Mercedesz Balazs,  James Barbosa,  Kai H Barck,  Brandon J Bravo,  Richard A D Carano,  James Darrow,  Douglas R Davies,  Laura E DeForge,  Lauri Diehl,  Ronald Ferrando,  Steven L Gallion,  Anthony M Giannetti,  Peter Gribling,  Vincent Hurez,  Sarah G Hymowitz,  Randall Jones,  Jeffrey E Kropf,  Wyne P Lee,  Patricia M Maciejewski,  Scott A Mitchell,  Hong Rong,  Bart L Staker,  J Andrew Whitney,  Sherry Yeh,  Wendy B Young,  Christine Yu,  Juan Zhang,  Karin Reif,  Kevin S Currie
Affiliations

Affiliation

  • 1 Department of Discovery Biology, CGI Pharmaceuticals, Branford, Connecticut, USA.
PMID: 21113169 DOI: 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.

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