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

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 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.

Authors:
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  1. (CGI)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYINDUSTRY
OSTI Identifier:
1025042
Resource Type:
Journal Article
Journal Name:
Nat. Chem. Biol.
Additional Journal Information:
Journal Volume: 7; Journal Issue: 01, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; DISEASES; ENZYMES; INFLAMMATION; LYMPHOKINES; MACROPHAGES; PHOSPHOTRANSFERASES; PRODUCTION; RHEUMATIC DISEASES; TARGETS; TYROSINE

Citation Formats

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., Emerald), and Genentech). Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. United States: N. p., 2011. Web. doi:10.1038/nchembio.481.
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., Emerald), & Genentech). Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. United States. doi:10.1038/nchembio.481.
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., Emerald), and Genentech). Tue . "Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis". United States. doi:10.1038/nchembio.481.
@article{osti_1025042,
title = {Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis},
author = {Di Paolo, Julie A. and Huang, Tao and Balazs, Mercedesz and Barbosa, James and Barck, Kai H. and Bravo, Brandon J. and Carano, Richard A.D. and Darrow, James and Davies, Douglas R. and DeForge, Laura E. and Diehl, Lauri and Ferrando, Ronald and Gallion, Steven L. and Giannetti, Anthony M. and Gribling, Peter and Hurez, Vincent and Hymowitz, Sarah G. and Jones, Randall and Kropf, Jeffrey E. and Lee, Wyne P. and Maciejewski, Patricia M. and Mitchell, Scott A. and Rong, Hong and Staker, Bart L. and Whitney, J. Andrew and Yeh, Sherry and Young, Wendy B. and Yu, Christine and Zhang, Juan and Reif, Karin and Currie, Kevin S. and Emerald) and Genentech)},
abstractNote = {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.},
doi = {10.1038/nchembio.481},
journal = {Nat. Chem. Biol.},
number = 01, 2011,
volume = 7,
place = {United States},
year = {2011},
month = {9}
}