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

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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, Davies, Douglas R, DeForge, Laura E, Diehl, Lauri, Ferrando, Ronald, Gallion, Steven L, Giannetti, Anthony M, Gribling, Peter, Hurez, Vincent, Hymowitz, Sarah G, Jones, Randall, Kropf, Jeffrey E, Lee, Wyne P, Maciejewski, Patricia M, Mitchell, Scott A, Rong, Hong, Staker, Bart L, Whitney, J Andrew, Yeh, Sherry, Young, Wendy B, Yu, Christine, Zhang, Juan, Reif, Karin, Currie, Kevin S·2011·Nature Chemical Biology

DOI 10.1038/nchembio.481

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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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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
ORCID: Huang, Tao
Barck, Kai H
Carano, Richard A D
Davies, Douglas R
Diehl, Lauri
Hurez, Vincent
Hymowitz, Sarah G
Lee, Wyne P
Maciejewski, Patricia M
Mitchell, Scott A
Rong, Hong
Staker, Bart L
Whitney, J Andrew
Yeh, Sherry
Yu, Christine
Zhang, Juan
Reif, Karin
Currie, Kevin S
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2010-11-28
Volume: 7
Issue: 1
Pages: 41-50
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.481
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: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

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