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Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis
Open accessAbstract
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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“The parent inhibitor CGI1746 used for our degraders does not inhibit HCK, 29”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [29]
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Cites
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Targeting Bruton's tyrosine kinase in B cell malignancies
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Metadata
- 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
- 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
- bronze
- doi.org
- Licence
- 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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