Skip to main content
Top
Published in: Arthritis Research & Therapy 4/2011

01-08-2011 | Editorial

More than just B-cell inhibition

Authors: Eric M Ruderman, Richard M Pope

Published in: Arthritis Research & Therapy | Issue 4/2011

Login to get access

Abstract

Despite tremendous advances in the therapy of rheumatoid arthritis (RA), there remains interest in oral agents that may offer benefits that are similar to, or better than, those of biologic therapies. In their paper, Chang and colleagues demonstrate the effectiveness of a Bruton tyrosine kinase (Btk) inhibitor in two models of RA. Btk inhibition impacts several pathways affecting both B-cell and macrophage activation, making it a promising target in RA. However, other kinase inhibitors have failed to transition from animal models to human therapy, so it remains to be seen whether a Btk inhibitor will have a role in the RA treatment armamentarium.
Literature
1.
go back to reference Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, Robinson WH, Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 2011, 13: R115-10.1186/ar3400.PubMedCentralCrossRefPubMed Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, Robinson WH, Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 2011, 13: R115-10.1186/ar3400.PubMedCentralCrossRefPubMed
2.
go back to reference Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, Christensson B, Berglöf A, Vihinen M, Nore BF, Smith CI: Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009, 228: 58-73. 10.1111/j.1600-065X.2008.00741.x.CrossRefPubMed Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, Christensson B, Berglöf A, Vihinen M, Nore BF, Smith CI: Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009, 228: 58-73. 10.1111/j.1600-065X.2008.00741.x.CrossRefPubMed
3.
go back to reference Kurosaki T, Hikida M: Tyrosine kinases and their substrates in B lymphocytes. Immunol Rev. 2009, 228: 132-148. 10.1111/j.1600-065X.2008.00748.x.CrossRefPubMed Kurosaki T, Hikida M: Tyrosine kinases and their substrates in B lymphocytes. Immunol Rev. 2009, 228: 132-148. 10.1111/j.1600-065X.2008.00748.x.CrossRefPubMed
4.
go back to reference Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP: Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996, 271: 822-825. 10.1126/science.271.5250.822.CrossRefPubMed Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP: Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996, 271: 822-825. 10.1126/science.271.5250.822.CrossRefPubMed
5.
go back to reference Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE, Diehl L, Ferrando R, Gallion SL, Giannetti AM, Gribling P, Hurez V, Hymowitz SG, Jones R, Kropf JE, Lee WP, Maciejewski PM, Mitchell SA, Rong H, Staker BL, Whitney JA, Yeh S, Young WB, Yu C, Zhang J, Reif K, Currie KS: Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011, 7: 41-50. 10.1038/nchembio.481.CrossRefPubMed Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE, Diehl L, Ferrando R, Gallion SL, Giannetti AM, Gribling P, Hurez V, Hymowitz SG, Jones R, Kropf JE, Lee WP, Maciejewski PM, Mitchell SA, Rong H, Staker BL, Whitney JA, Yeh S, Young WB, Yu C, Zhang J, Reif K, Currie KS: Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011, 7: 41-50. 10.1038/nchembio.481.CrossRefPubMed
6.
go back to reference Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, Uckun FM: Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem. 1999, 274: 9587-9599. 10.1074/jbc.274.14.9587.CrossRefPubMed Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, Uckun FM: Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem. 1999, 274: 9587-9599. 10.1074/jbc.274.14.9587.CrossRefPubMed
7.
go back to reference Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT: Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem. 2007, 2: 58-61.CrossRefPubMed Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT: Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem. 2007, 2: 58-61.CrossRefPubMed
8.
go back to reference Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010, 107: 13075-13080. 10.1073/pnas.1004594107.PubMedCentralCrossRefPubMed Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010, 107: 13075-13080. 10.1073/pnas.1004594107.PubMedCentralCrossRefPubMed
9.
go back to reference Horwood NJ, Mahon T, McDaid JP, Campbell J, Mano H, Brennan FM, Webster D, Foxwell BM: Bruton's tyrosine kinase is required for lipopolysaccharideinduced tumor necrosis factor alpha production. J Exp Med. 2003, 197: 1603-1611. 10.1084/jem.20021845.PubMedCentralCrossRefPubMed Horwood NJ, Mahon T, McDaid JP, Campbell J, Mano H, Brennan FM, Webster D, Foxwell BM: Bruton's tyrosine kinase is required for lipopolysaccharideinduced tumor necrosis factor alpha production. J Exp Med. 2003, 197: 1603-1611. 10.1084/jem.20021845.PubMedCentralCrossRefPubMed
10.
go back to reference Vijayan V, Baumgart-Vogt E, Naidu S, Qian G, Immenschuh S: Bruton's tyrosine kinase is required for TLR-dependent heme oxygenase-1 gene activation via Nrf2 in macrophages. J Immunol. 2011, 187: 817-827. 10.4049/jimmunol.1003631.CrossRefPubMed Vijayan V, Baumgart-Vogt E, Naidu S, Qian G, Immenschuh S: Bruton's tyrosine kinase is required for TLR-dependent heme oxygenase-1 gene activation via Nrf2 in macrophages. J Immunol. 2011, 187: 817-827. 10.4049/jimmunol.1003631.CrossRefPubMed
11.
go back to reference Huang Q, Pope RM: Toll-like receptor signaling: a potential link among rheumatoid arthritis, systemic lupus, and atherosclerosis. J Leukoc Biol. 2010, 88: 253-262. 10.1189/jlb.0310126.PubMedCentralCrossRefPubMed Huang Q, Pope RM: Toll-like receptor signaling: a potential link among rheumatoid arthritis, systemic lupus, and atherosclerosis. J Leukoc Biol. 2010, 88: 253-262. 10.1189/jlb.0310126.PubMedCentralCrossRefPubMed
12.
go back to reference Hammaker D, Firestein GS: "Go upstream, young man": lessons learned from the p38 saga. Ann Rheum Dis. 2010, 69 (Suppl 1): i77-82. 10.1136/ard.2009.119479.PubMedCentralCrossRefPubMed Hammaker D, Firestein GS: "Go upstream, young man": lessons learned from the p38 saga. Ann Rheum Dis. 2010, 69 (Suppl 1): i77-82. 10.1136/ard.2009.119479.PubMedCentralCrossRefPubMed
13.
go back to reference Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leaffer D, Kim YN, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, Wong BR: Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008, 327: 610-619. 10.1124/jpet.108.139006.CrossRefPubMed Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leaffer D, Kim YN, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, Wong BR: Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008, 327: 610-619. 10.1124/jpet.108.139006.CrossRefPubMed
Metadata
Title
More than just B-cell inhibition
Authors
Eric M Ruderman
Richard M Pope
Publication date
01-08-2011
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 4/2011
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3439

Other articles of this Issue 4/2011

Arthritis Research & Therapy 4/2011 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine