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
  • 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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