Cited by 394Rheumatoid Arthritis Research and TherapiesNatural Compounds in Disease TreatmentProtein Kinase Regulation and GTPase Signaling

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

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Di Paolo, Julie A, Huang, Tao, Balazs, Mercedesz, Barbosa, James, Barck, Kai H, Bravo, Brandon J, Carano, Richard A D, Darrow, James +23 more·2011·Nature Chemical Biology

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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  1. Currie, K.S., DeSimone, R.W., Mitchell, S.A. & Pippin, D.A. Certain heterocyclic substituted imidazo[1,2-a]pyrazin-8-yl compounds and methods of inhibition of Bruton's tyrosine kinase by such compounds. US Patent 7,393,848 (2008).

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Authors
Di Paolo, J. A., Huang, T., Balazs, M., Barbosa, J., Barck, K. H., Bravo, B. J., Carano, R. A. D., Darrow, J., Davies, D. R., DeForge, L. E., Diehl, L., Ferrando, R., Gallion, S. L., Giannetti, A. M., Gribling, P., Hurez, V., Hymowitz, S. G., Jones, R., Kropf, J. E., Lee, W. P., Maciejewski, P. M., Mitchell, S. A., Rong, H., Staker, B. L., Whitney, J. A., Yeh, S., Young, W. B., Yu, C., Zhang, J., Reif, K., & Currie, K. S.
Affiliations
  • Genentech (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Reif, Karin
  • Currie, Kevin S
Venue
Nature Chemical Biology
Published
2010-11-28
Volume
7
Issue
1
Pages
41-50
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
OpenAlex
W2093522627
Cited by
340
References
50
Citations by year
2026: 15 · 2025: 16 · 2024: 13 · 2023: 14 · 2022: 26 · 2021: 35 · 2020: 29 · 2019: 25 · 2018: 22 · 2017: 33 · 2016: 22 · 2015: 26 · 2014: 23 · 2013: 16 · 2012: 15
FWCI
9.81
Type
journal article
Language
en
Open access
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Genentech
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Bruton's tyrosine kinase, BTK inhibition, rheumatoid arthritis, inflammatory arthritis, B cell receptor signaling, FcγRIII, macrophage cytokine production, TNF-α, IL-1β, interleukin-6, B cell proliferation, collagen-induced arthritis
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Animals, Arthritis, Experimental, Arthritis, Rheumatoid, Autoantibodies, B-Lymphocytes, Benzamides, Enzyme Activation, Phosphorylation, Protein-Tyrosine Kinases, Tumor Necrosis Factor-alpha, Interleukin-6, Bridged Bicyclo Compounds, Heterocyclic, Myeloid Cells, Protein Kinase Inhibitors, Cell Proliferation, Mice, Interleukin-1beta

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