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

被引：281

作者：

Di Paolo, Julie A. ^{[2
]}

Huang, Tao ^{[1
]}

Balazs, Mercedesz ^{[1
]}

Barbosa, James ^{[8
]}

Barck, Kai H. ^{[3
]}

Bravo, Brandon J. ^{[4
]}

Carano, Richard A. D. ^{[3
]}

Darrow, James ^{[5
]}

Davies, Douglas R. ^{[6
]}

DeForge, Laura E. ^{[7
]}

Diehl, Lauri ^{[8
]}

Ferrando, Ronald ^{[8
]}

Gallion, Steven L. ^{[9
]}

Giannetti, Anthony M. ^{[4
]}

Gribling, Peter ^{[1
]}

Hurez, Vincent ^{[1
]}

Hymowitz, Sarah G. ^{[10
]}

Jones, Randall ^{[2
]}

Kropf, Jeffrey E. ^{[5
]}

Lee, Wyne P. ^{[1
]}

Maciejewski, Patricia M. ^{[2
]}

Mitchell, Scott A. ^{[5
]}

Rong, Hong ^{[2
]}

Staker, Bart L. ^{[6
]}

Whitney, J. Andrew ^{[2
]}

Yeh, Sherry ^{[7
]}

Young, Wendy B. ^{[11
]}

Yu, Christine ^{[10
]}

Zhang, Juan ^{[1
]}

Reif, Karin ^{[1
]}

Currie, Kevin S. ^{[5
]}

机构：

[1] Genentech Inc, Dept Immunobiol, San Francisco, CA 94080 USA

[2] CGI Pharmaceut, Dept Discovery Biol, Branford, CT USA

[3] Genentech Inc, Dept Tumor Biol & Angiogenesis, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem Pharmacol, San Francisco, CA 94080 USA

[5] CGI Pharmaceut, Dept Med Chem, Branford, CT USA

[6] Emerald BioStruct, Bainbridge Isl, WA USA

[7] Genentech Inc, Dept Assay & Automat Technol, San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[9] Computat Chem CGI Pharmaceut, Branford, CT USA

[10] Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA

[11] Genentech Inc, Dept Med Chem, San Francisco, CA 94080 USA

来源：

NATURE CHEMICAL BIOLOGY | 2011年 / 7卷 / 01期

关键词：

BRUTONS TYROSINE KINASE; COLLAGEN-INDUCED ARTHRITIS; FC-GAMMA RECEPTORS; RHEUMATOID-ARTHRITIS; II COLLAGEN; CITRULLINATED PROTEINS; ACTIVATION; PHOSPHORYLATION; MACROPHAGES; INDUCTION;

D O I：

10.1038/NCHEMBIO.481

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Fc gamma RIII-induced TNF alpha, IL-1 beta and IL-6 production. Accordingly, in myeloid- and Fc gamma R-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.

引用

页码：41 / 50

页数：10

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