Skip to main content
Top
Published in: Drugs 2/2013

01-02-2013 | Leading Article

Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis

Authors: Verica Paunovic, Margaret M. Harnett

Published in: Drugs | Issue 2/2013

Login to get access

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. Methotrexate, the standard disease-modifying anti-rheumatic drug (DMARD), has shown a gradual loss of efficacy in a significant proportion of patients, probably due to the onset of drug resistance, and thus it was hoped that the development of biologics would revolutionise RA management. Even though biologics have improved the therapy of patients refractive to DMARDs, they require parenteral administration and may leave patients open to serious infection and cancer. Therefore, attention has also been focused on inhibitors of mitogen-activated protein kinases (MAPKs), signalling enzymes that play key roles in pathogenic cytokine production, and their downstream effector pathways, in order to create safe and effective oral drugs. This article therefore provides an overview of the structure and function of MAPKs and their role in the pathogenesis of RA as context to describing the advances in the development of specific, druggable MAPK inhibitors. Their potential as therapies in the management of RA is also discussed.
Literature
1.
go back to reference McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.PubMedCrossRef McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.PubMedCrossRef
2.
go back to reference McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42.PubMedCrossRef McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42.PubMedCrossRef
3.
go back to reference Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45.PubMedCrossRef Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45.PubMedCrossRef
4.
go back to reference Cai L, Yin JP, Starovasnik MA, Hogue DA, Hillan KJ, Mort JS, et al. Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine. 2001;16(1):10–21.PubMedCrossRef Cai L, Yin JP, Starovasnik MA, Hogue DA, Hillan KJ, Mort JS, et al. Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine. 2001;16(1):10–21.PubMedCrossRef
5.
go back to reference Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1(2):102–10.PubMedCrossRef Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1(2):102–10.PubMedCrossRef
6.
go back to reference Zhou FH, Foster BK, Zhou XF, Cowin AJ, Xian CJ. TNF-alpha mediates p38 MAP kinase activation and negatively regulates bone formation at the injured growth plate in rats. J Bone Miner Res. 2006;21(7):1075–88.PubMedCrossRef Zhou FH, Foster BK, Zhou XF, Cowin AJ, Xian CJ. TNF-alpha mediates p38 MAP kinase activation and negatively regulates bone formation at the injured growth plate in rats. J Bone Miner Res. 2006;21(7):1075–88.PubMedCrossRef
7.
go back to reference Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol. 1984;11(6):760–3.PubMed Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol. 1984;11(6):760–3.PubMed
8.
go back to reference Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312(13):818–22.PubMedCrossRef Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312(13):818–22.PubMedCrossRef
9.
go back to reference Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS, Guttadauria M, Yarboro C, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthr Rheum. 1985;28(7):721–30.CrossRef Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS, Guttadauria M, Yarboro C, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthr Rheum. 1985;28(7):721–30.CrossRef
10.
go back to reference Morgan C, Lunt M, Brightwell H, Bradburn P, Fallow W, Lay M, et al. Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis. 2003;62(1):15–9.PubMedCrossRef Morgan C, Lunt M, Brightwell H, Bradburn P, Fallow W, Lay M, et al. Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis. 2003;62(1):15–9.PubMedCrossRef
11.
go back to reference Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 2012;91(1):30–43.PubMedCrossRef Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 2012;91(1):30–43.PubMedCrossRef
12.
go back to reference Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis. 2011;70(5):727–32.PubMedCrossRef Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis. 2011;70(5):727–32.PubMedCrossRef
13.
go back to reference Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2(9):717–26.PubMedCrossRef Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2(9):717–26.PubMedCrossRef
14.
go back to reference Cohen S. Small molecular therapies for rheumatoid arthritis: where do we stand? Expert Opin Investig Drugs. 2012;21(1):23–31.PubMedCrossRef Cohen S. Small molecular therapies for rheumatoid arthritis: where do we stand? Expert Opin Investig Drugs. 2012;21(1):23–31.PubMedCrossRef
15.
go back to reference Liu JO. The yins of T cell activation. Sci STKE. 2005;4(265):re1. Liu JO. The yins of T cell activation. Sci STKE. 2005;4(265):re1.
16.
go back to reference Harnett MM, Katz E, Ford CA. Differential signalling during B-cell maturation. Immunol Lett. 2005;98(1):33–44.PubMedCrossRef Harnett MM, Katz E, Ford CA. Differential signalling during B-cell maturation. Immunol Lett. 2005;98(1):33–44.PubMedCrossRef
17.
18.
go back to reference Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology. 2003;109(3):415–25.PubMedCrossRef Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology. 2003;109(3):415–25.PubMedCrossRef
19.
go back to reference Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J Immunol. 1999;163(12):6403–12.PubMed Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J Immunol. 1999;163(12):6403–12.PubMed
20.
go back to reference Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739–46.PubMedCrossRef Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739–46.PubMedCrossRef
21.
go back to reference Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.PubMedCrossRef Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.PubMedCrossRef
22.
go back to reference Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.PubMedCrossRef Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.PubMedCrossRef
23.
go back to reference Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997;90(5):859–69.PubMedCrossRef Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997;90(5):859–69.PubMedCrossRef
24.
go back to reference Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene. 2007;26(22):3240–53.PubMedCrossRef Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene. 2007;26(22):3240–53.PubMedCrossRef
25.
go back to reference Biondi RM, Nebreda AR. Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem J. 2003;372(Pt 1):1–13.PubMedCrossRef Biondi RM, Nebreda AR. Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem J. 2003;372(Pt 1):1–13.PubMedCrossRef
26.
go back to reference Tanoue T, Nishida E. Molecular recognitions in the MAP kinase cascades. Cell Signal. 2003;15(5):455–62.PubMedCrossRef Tanoue T, Nishida E. Molecular recognitions in the MAP kinase cascades. Cell Signal. 2003;15(5):455–62.PubMedCrossRef
27.
go back to reference Akella R, Moon TM, Goldsmith EJ. Unique MAP Kinase binding sites. Biochim Biophys Acta. 2008;1784(1):48–55.PubMedCrossRef Akella R, Moon TM, Goldsmith EJ. Unique MAP Kinase binding sites. Biochim Biophys Acta. 2008;1784(1):48–55.PubMedCrossRef
28.
go back to reference Powers JC, Asgian JL, Ekici OD, James KE. Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev. 2002;102(12):4639–750.PubMedCrossRef Powers JC, Asgian JL, Ekici OD, James KE. Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev. 2002;102(12):4639–750.PubMedCrossRef
29.
go back to reference Morrison DK, Davis RJ. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003;19:91–118.PubMedCrossRef Morrison DK, Davis RJ. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003;19:91–118.PubMedCrossRef
30.
go back to reference Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene. 2007;26(22):3100–12.PubMedCrossRef Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene. 2007;26(22):3100–12.PubMedCrossRef
31.
go back to reference Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993;7(11):2135–48.PubMedCrossRef Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993;7(11):2135–48.PubMedCrossRef
32.
go back to reference Ortega-Perez I, Cano E, Were F, Villar M, Vazquez J, Redondo JM. c-Jun N-terminal kinase (JNK) positively regulates NFATc2 transactivation through phosphorylation within the N-terminal regulatory domain. J Biol Chem. 2005;280(21):20867–78.PubMedCrossRef Ortega-Perez I, Cano E, Were F, Villar M, Vazquez J, Redondo JM. c-Jun N-terminal kinase (JNK) positively regulates NFATc2 transactivation through phosphorylation within the N-terminal regulatory domain. J Biol Chem. 2005;280(21):20867–78.PubMedCrossRef
33.
go back to reference Cavigelli M, Dolfi F, Claret FX, Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995;14(23):5957–64.PubMed Cavigelli M, Dolfi F, Claret FX, Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995;14(23):5957–64.PubMed
34.
go back to reference van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995;14(8):1798–811.PubMed van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995;14(8):1798–811.PubMed
35.
go back to reference Treisman R. Journey to the surface of the cell: Fos regulation and the SRE. EMBO J. 1995;14(20):4905–13.PubMed Treisman R. Journey to the surface of the cell: Fos regulation and the SRE. EMBO J. 1995;14(20):4905–13.PubMed
36.
go back to reference Fuchs SY, Adler V, Pincus MR, Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc Natl Acad Sci USA. 1998;95(18):10541–6.PubMedCrossRef Fuchs SY, Adler V, Pincus MR, Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc Natl Acad Sci USA. 1998;95(18):10541–6.PubMedCrossRef
37.
go back to reference Lu G, Kang YJ, Han J, Herschman HR, Stefani E, Wang Y. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem. 2006;281(9):6087–95.PubMedCrossRef Lu G, Kang YJ, Han J, Herschman HR, Stefani E, Wang Y. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem. 2006;281(9):6087–95.PubMedCrossRef
38.
go back to reference Saxena M, Mustelin T. Extracellular signals and scores of phosphatases: all roads lead to MAP kinase. Semin Immunol. 2000;12(4):387–96.PubMedCrossRef Saxena M, Mustelin T. Extracellular signals and scores of phosphatases: all roads lead to MAP kinase. Semin Immunol. 2000;12(4):387–96.PubMedCrossRef
39.
go back to reference Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY. The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem. 2002;277(35):31818–25.PubMedCrossRef Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY. The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem. 2002;277(35):31818–25.PubMedCrossRef
40.
go back to reference Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000;14(1):6–16.PubMed Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000;14(1):6–16.PubMed
41.
go back to reference Masuda K, Shima H, Watanabe M, Kikuchi K. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001;276(42):39002–11.PubMedCrossRef Masuda K, Shima H, Watanabe M, Kikuchi K. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001;276(42):39002–11.PubMedCrossRef
42.
go back to reference Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J Biol Chem. 2004;279(40):41882–91.PubMedCrossRef Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J Biol Chem. 2004;279(40):41882–91.PubMedCrossRef
43.
go back to reference Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7(3):274–83.PubMedCrossRef Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7(3):274–83.PubMedCrossRef
44.
go back to reference Fransen J, van Riel PL. Outcome measures in inflammatory rheumatic diseases. Arthr Res Ther. 2009;11(5):244.CrossRef Fransen J, van Riel PL. Outcome measures in inflammatory rheumatic diseases. Arthr Res Ther. 2009;11(5):244.CrossRef
45.
go back to reference Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, et al. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2010;30(4):443–9.PubMedCrossRef Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, et al. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2010;30(4):443–9.PubMedCrossRef
46.
go back to reference Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol. 2005;175(12):8280–6.PubMed Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol. 2005;175(12):8280–6.PubMed
47.
go back to reference Kim YG, Lee CK, Kim SH, Cho WS, Mun SH, Yoo B. Interleukin-32gamma enhances the production of IL-6 and IL-8 in fibroblast-like synoviocytes via Erk1/2 activation. J Clin Immunol. 2010;30(2):260–7.PubMedCrossRef Kim YG, Lee CK, Kim SH, Cho WS, Mun SH, Yoo B. Interleukin-32gamma enhances the production of IL-6 and IL-8 in fibroblast-like synoviocytes via Erk1/2 activation. J Clin Immunol. 2010;30(2):260–7.PubMedCrossRef
48.
go back to reference Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, et al. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthr Rheum. 2000;43(11):2501–12.CrossRef Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, et al. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthr Rheum. 2000;43(11):2501–12.CrossRef
49.
go back to reference Geppert TD, Whitehurst CE, Thompson P, Beutler B. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol Med. 1994;1(1):93–103.PubMed Geppert TD, Whitehurst CE, Thompson P, Beutler B. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol Med. 1994;1(1):93–103.PubMed
50.
go back to reference Barchowsky A, Frleta D, Vincenti MP. Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts. Cytokine. 2000;12(10):1469–79.PubMedCrossRef Barchowsky A, Frleta D, Vincenti MP. Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts. Cytokine. 2000;12(10):1469–79.PubMedCrossRef
51.
go back to reference Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108(1):73–81.PubMed Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108(1):73–81.PubMed
52.
go back to reference Pelletier JP, Fernandes JC, Brunet J, Moldovan F, Schrier D, Flory C, et al. In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthr Rheum. 2003;48(6):1582–93.CrossRef Pelletier JP, Fernandes JC, Brunet J, Moldovan F, Schrier D, Flory C, et al. In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthr Rheum. 2003;48(6):1582–93.CrossRef
53.
go back to reference Liacini A, Sylvester J, Li WQ, Huang W, Dehnade F, Ahmad M, et al. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208–17.PubMedCrossRef Liacini A, Sylvester J, Li WQ, Huang W, Dehnade F, Ahmad M, et al. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208–17.PubMedCrossRef
54.
go back to reference Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthr Rheum. 2007;56(10):3347–57.CrossRef Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthr Rheum. 2007;56(10):3347–57.CrossRef
55.
go back to reference Singh K, Deshpande P, Pryshchep S, Colmegna I, Liarski V, Weyand CM, et al. ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. J Immunol. 2009;183(12):8258–67.PubMedCrossRef Singh K, Deshpande P, Pryshchep S, Colmegna I, Liarski V, Weyand CM, et al. ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. J Immunol. 2009;183(12):8258–67.PubMedCrossRef
56.
go back to reference Lindstrom TM, Robinson WH. A multitude of kinases: which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin North Am. 2010;36(2):367–83.PubMedCrossRef Lindstrom TM, Robinson WH. A multitude of kinases: which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin North Am. 2010;36(2):367–83.PubMedCrossRef
57.
go back to reference Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem Biophys Res Commun. 2005;336(1):357–63.PubMedCrossRef Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem Biophys Res Commun. 2005;336(1):357–63.PubMedCrossRef
58.
go back to reference Ohori M. ERK inhibitors as a potential new therapy for rheumatoid arthritis. Drug News Perspect. 2008;21(5):245–50.PubMedCrossRef Ohori M. ERK inhibitors as a potential new therapy for rheumatoid arthritis. Drug News Perspect. 2008;21(5):245–50.PubMedCrossRef
59.
go back to reference Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2007;374(4):311–6.PubMedCrossRef Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2007;374(4):311–6.PubMedCrossRef
60.
go back to reference Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, et al. Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. J Biol Chem. 2005;280(25):23748–57.PubMedCrossRef Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, et al. Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. J Biol Chem. 2005;280(25):23748–57.PubMedCrossRef
61.
go back to reference Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2000;103(7):1071–83.PubMedCrossRef Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2000;103(7):1071–83.PubMedCrossRef
62.
go back to reference Hall JP, Kurdi Y, Hsu S, Cuozzo J, Liu J, Telliez JB, et al. Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem. 2007;282(46):33295–304.PubMedCrossRef Hall JP, Kurdi Y, Hsu S, Cuozzo J, Liu J, Telliez JB, et al. Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem. 2007;282(46):33295–304.PubMedCrossRef
63.
go back to reference Green N, Hu Y, Janz K, Li HQ, Kaila N, Guler S, et al. Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles. J Med Chem. 2007;50(19):4728–45.PubMedCrossRef Green N, Hu Y, Janz K, Li HQ, Kaila N, Guler S, et al. Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles. J Med Chem. 2007;50(19):4728–45.PubMedCrossRef
64.
go back to reference Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol. 2002;21(3):251–62.PubMedCrossRef Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol. 2002;21(3):251–62.PubMedCrossRef
65.
go back to reference Sundarrajan M, Boyle DL, Chabaud-Riou M, Hammaker D, Firestein GS. Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthr Rheum. 2003;48(9):2450–60.CrossRef Sundarrajan M, Boyle DL, Chabaud-Riou M, Hammaker D, Firestein GS. Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthr Rheum. 2003;48(9):2450–60.CrossRef
66.
go back to reference Inoue T, Hammaker D, Boyle DL, Firestein GS. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthr Rheum. 2006;54(7):2127–35.CrossRef Inoue T, Hammaker D, Boyle DL, Firestein GS. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthr Rheum. 2006;54(7):2127–35.CrossRef
67.
go back to reference Lee SI, Boyle DL, Berdeja A, Firestein GS. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthr Res Ther. 2012;14(1):R38.CrossRef Lee SI, Boyle DL, Berdeja A, Firestein GS. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthr Res Ther. 2012;14(1):R38.CrossRef
68.
go back to reference Maroney AC, Finn JP, Bozyczko-Coyne D, O’Kane TM, Neff NT, Tolkovsky AM, et al. CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults. J Neurochem. 1999;73(5):1901–12.PubMed Maroney AC, Finn JP, Bozyczko-Coyne D, O’Kane TM, Neff NT, Tolkovsky AM, et al. CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults. J Neurochem. 1999;73(5):1901–12.PubMed
69.
go back to reference Maroney AC, Finn JP, Connors TJ, Durkin JT, Angeles T, Gessner G, et al. Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem. 2001;276(27):25302–8.PubMedCrossRef Maroney AC, Finn JP, Connors TJ, Durkin JT, Angeles T, Gessner G, et al. Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem. 2001;276(27):25302–8.PubMedCrossRef
70.
go back to reference Cui J, Zhang M, Zhang YQ, Xu ZH. JNK pathway: diseases and therapeutic potential. Acta Pharmacol Sin. 2007;28(5):601–8.PubMedCrossRef Cui J, Zhang M, Zhang YQ, Xu ZH. JNK pathway: diseases and therapeutic potential. Acta Pharmacol Sin. 2007;28(5):601–8.PubMedCrossRef
71.
go back to reference Wang W, Ma C, Mao Z, Li M. JNK inhibition as a potential strategy in treating Parkinson’s disease. Drug News Perspect. 2004;17(10):646–54.PubMedCrossRef Wang W, Ma C, Mao Z, Li M. JNK inhibition as a potential strategy in treating Parkinson’s disease. Drug News Perspect. 2004;17(10):646–54.PubMedCrossRef
72.
go back to reference Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 2001;98(24):13681–6.PubMedCrossRef Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 2001;98(24):13681–6.PubMedCrossRef
73.
go back to reference Ruckle T, Biamonte M, Grippi-Vallotton T, Arkinstall S, Cambet Y, Camps M, et al. Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J Med Chem. 2004;47(27):6921–34.PubMedCrossRef Ruckle T, Biamonte M, Grippi-Vallotton T, Arkinstall S, Cambet Y, Camps M, et al. Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J Med Chem. 2004;47(27):6921–34.PubMedCrossRef
74.
go back to reference Gaillard P, Jeanclaude-Etter I, Ardissone V, Arkinstall S, Cambet Y, Camps M, et al. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem. 2005;48(14):4596–607.PubMedCrossRef Gaillard P, Jeanclaude-Etter I, Ardissone V, Arkinstall S, Cambet Y, Camps M, et al. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem. 2005;48(14):4596–607.PubMedCrossRef
75.
go back to reference Denninger K, Rasmussen S, Larsen JM, Orskov C, Seier Poulsen S, Sorensen P, et al. JNK1, but not JNK2, is required in two mechanistically distinct models of inflammatory arthritis. Am J Pathol. 2011;179(4):1884–93.PubMedCrossRef Denninger K, Rasmussen S, Larsen JM, Orskov C, Seier Poulsen S, Sorensen P, et al. JNK1, but not JNK2, is required in two mechanistically distinct models of inflammatory arthritis. Am J Pathol. 2011;179(4):1884–93.PubMedCrossRef
76.
go back to reference Koller M, Hayer S, Redlich K, Ricci R, David JP, Steiner G, et al. JNK1 is not essential for TNF-mediated joint disease. Arthr Res Ther. 2005;7(1):R166–73.CrossRef Koller M, Hayer S, Redlich K, Ricci R, David JP, Steiner G, et al. JNK1 is not essential for TNF-mediated joint disease. Arthr Res Ther. 2005;7(1):R166–73.CrossRef
77.
go back to reference Gee E, Milkiewicz M, Haas TL. p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. J Cell Physiol. 2010;222(1):120–6.PubMedCrossRef Gee E, Milkiewicz M, Haas TL. p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. J Cell Physiol. 2010;222(1):120–6.PubMedCrossRef
78.
go back to reference Rousseau D, Cannella D, Boulaire J, Fitzgerald P, Fotedar A, Fotedar R. Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway. Oncogene. 1999;18(30):4313–25.PubMedCrossRef Rousseau D, Cannella D, Boulaire J, Fitzgerald P, Fotedar A, Fotedar R. Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway. Oncogene. 1999;18(30):4313–25.PubMedCrossRef
79.
go back to reference Duch A, de Nadal E, Posas F. The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. FEBS Lett. 2012;586(18):2925–31.PubMedCrossRef Duch A, de Nadal E, Posas F. The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. FEBS Lett. 2012;586(18):2925–31.PubMedCrossRef
80.
go back to reference Joaquin M, Gubern A, Gonzalez-Nunez D, Josue Ruiz E, Ferreiro I, de Nadal E, et al. The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress. EMBO J. 2012;31(13):2952–64.PubMedCrossRef Joaquin M, Gubern A, Gonzalez-Nunez D, Josue Ruiz E, Ferreiro I, de Nadal E, et al. The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress. EMBO J. 2012;31(13):2952–64.PubMedCrossRef
81.
go back to reference Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hu WY, et al. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol Cell Biol. 2012;32(3):606–18.PubMedCrossRef Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hu WY, et al. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol Cell Biol. 2012;32(3):606–18.PubMedCrossRef
82.
go back to reference Lee JC, Young PR. Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J Leukoc Biol. 1996;59(2):152–7.PubMed Lee JC, Young PR. Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J Leukoc Biol. 1996;59(2):152–7.PubMed
83.
go back to reference Tokuda H, Kanno Y, Ishisaki A, Takenaka M, Harada A, Kozawa O. Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. J Cell Biochem. 2004;91(5):1053–61.PubMedCrossRef Tokuda H, Kanno Y, Ishisaki A, Takenaka M, Harada A, Kozawa O. Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. J Cell Biochem. 2004;91(5):1053–61.PubMedCrossRef
84.
go back to reference Westra J, Limburg PC, de Boer P, van Rijswijk MH. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann Rheum Dis. 2004;63(11):1453–9.PubMedCrossRef Westra J, Limburg PC, de Boer P, van Rijswijk MH. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann Rheum Dis. 2004;63(11):1453–9.PubMedCrossRef
85.
go back to reference Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, et al. A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol. 2004;173(11):6928–37.PubMed Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, et al. A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol. 2004;173(11):6928–37.PubMed
86.
go back to reference Young P, McDonnell P, Dunnington D, Hand A, Laydon J, Lee J. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions. 1993;39 Spec No:C67–9. Young P, McDonnell P, Dunnington D, Hand A, Laydon J, Lee J. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions. 1993;39 Spec No:C67–9.
87.
go back to reference Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. J Immunol. 1999;162(9):5367–73.PubMed Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. J Immunol. 1999;162(9):5367–73.PubMed
88.
go back to reference Chae HJ, Chae SW, Chin HY, Bang BG, Cho SB, Han KS, et al. The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts. Bone. 2001;28(1):45–53.PubMedCrossRef Chae HJ, Chae SW, Chin HY, Bang BG, Cho SB, Han KS, et al. The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts. Bone. 2001;28(1):45–53.PubMedCrossRef
89.
go back to reference Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 2005;115(2):282–90.PubMed Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 2005;115(2):282–90.PubMed
90.
go back to reference Rossa C, Ehmann K, Liu M, Patil C, Kirkwood KL. MKK3/6-p38 MAPK signaling is required for IL-1beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells. J Interferon Cytokine Res. 2006;26(10):719–29.PubMedCrossRef Rossa C, Ehmann K, Liu M, Patil C, Kirkwood KL. MKK3/6-p38 MAPK signaling is required for IL-1beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells. J Interferon Cytokine Res. 2006;26(10):719–29.PubMedCrossRef
91.
go back to reference Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990;145(10):3297–303.PubMed Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990;145(10):3297–303.PubMed
92.
go back to reference Thouverey C, Caverzasio J. The p38alpha MAPK positively regulates osteoblast function and postnatal bone acquisition. Cell Mol Life Sci. 2012;69(18):3115–25.PubMedCrossRef Thouverey C, Caverzasio J. The p38alpha MAPK positively regulates osteoblast function and postnatal bone acquisition. Cell Mol Life Sci. 2012;69(18):3115–25.PubMedCrossRef
93.
go back to reference Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem. 2000;275(40):31155–61.PubMedCrossRef Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem. 2000;275(40):31155–61.PubMedCrossRef
94.
go back to reference McLay LM, Halley F, Souness JE, McKenna J, Benning V, Birrell M, et al. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem. 2001;9(2):537–54.PubMedCrossRef McLay LM, Halley F, Souness JE, McKenna J, Benning V, Birrell M, et al. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem. 2001;9(2):537–54.PubMedCrossRef
95.
go back to reference Mbalaviele G, Anderson G, Jones A, De Ciechi P, Settle S, Mnich S, et al. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther. 2006;317(3):1044–53.PubMedCrossRef Mbalaviele G, Anderson G, Jones A, De Ciechi P, Settle S, Mnich S, et al. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther. 2006;317(3):1044–53.PubMedCrossRef
96.
go back to reference Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, et al. A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther. 2006;318(1):132–41.PubMedCrossRef Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, et al. A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther. 2006;318(1):132–41.PubMedCrossRef
97.
go back to reference Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthr Rheum. 2003;48(9):2670–81.CrossRef Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthr Rheum. 2003;48(9):2670–81.CrossRef
98.
go back to reference Badger AM, Griswold DE, Kapadia R, Blake S, Swift BA, Hoffman SJ, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthr Rheum. 2000;43(1):175–83.CrossRef Badger AM, Griswold DE, Kapadia R, Blake S, Swift BA, Hoffman SJ, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthr Rheum. 2000;43(1):175–83.CrossRef
99.
go back to reference Korb A, Tohidast-Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthr Rheum. 2006;54(9):2745–56.CrossRef Korb A, Tohidast-Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthr Rheum. 2006;54(9):2745–56.CrossRef
100.
go back to reference Fijen JW, Zijlstra JG, De Boer P, Spanjersberg R, Tervaert JW, Van Der Werf TS, et al. Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol. 2001;124(1):16–20.PubMedCrossRef Fijen JW, Zijlstra JG, De Boer P, Spanjersberg R, Tervaert JW, Van Der Werf TS, et al. Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol. 2001;124(1):16–20.PubMedCrossRef
101.
go back to reference Parasrampuria DA, de Boer P, Desai-Krieger D, Chow AT, Jones CR. Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study. J Clin Pharmacol. 2003;43(4):406–13.PubMedCrossRef Parasrampuria DA, de Boer P, Desai-Krieger D, Chow AT, Jones CR. Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study. J Clin Pharmacol. 2003;43(4):406–13.PubMedCrossRef
102.
go back to reference Genovese MC, Cohen SB, Wofsy D, Weinblatt ME, Firestein GS, Brahn E, et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846–54.PubMedCrossRef Genovese MC, Cohen SB, Wofsy D, Weinblatt ME, Firestein GS, Brahn E, et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846–54.PubMedCrossRef
103.
go back to reference Haddad JJ. VX-745. Vertex pharmaceuticals. Curr Opin Investig Drugs. 2001;2(8):1070–6.PubMed Haddad JJ. VX-745. Vertex pharmaceuticals. Curr Opin Investig Drugs. 2001;2(8):1070–6.PubMed
104.
go back to reference Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthr Rheum. 2009;60(5):1232–41.CrossRef Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthr Rheum. 2009;60(5):1232–41.CrossRef
105.
go back to reference Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010;53(6):2345–53.PubMedCrossRef Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010;53(6):2345–53.PubMedCrossRef
106.
go back to reference Schreiber S, Feagan B, D’Haens G, Colombel JF, Geboes K, Yurcov M, et al. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(3):325–34.PubMedCrossRef Schreiber S, Feagan B, D’Haens G, Colombel JF, Geboes K, Yurcov M, et al. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(3):325–34.PubMedCrossRef
107.
go back to reference Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, et al. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008;327(3):610–9.PubMedCrossRef Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, et al. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008;327(3):610–9.PubMedCrossRef
108.
go back to reference Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthr Rheum. 2009;60(2):335–44.CrossRef Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthr Rheum. 2009;60(2):335–44.CrossRef
109.
go back to reference Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12(25):2979–94.PubMedCrossRef Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12(25):2979–94.PubMedCrossRef
110.
go back to reference Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther. 2002;93(2–3):79–98.PubMedCrossRef Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther. 2002;93(2–3):79–98.PubMedCrossRef
111.
go back to reference Fischer S, Koeberle SC, Laufer SA. p38alpha mitogen-activated protein kinase inhibitors, a patent review (2005–2011). Expert Opin Ther Pat. 2011;21(12):1843–66.PubMedCrossRef Fischer S, Koeberle SC, Laufer SA. p38alpha mitogen-activated protein kinase inhibitors, a patent review (2005–2011). Expert Opin Ther Pat. 2011;21(12):1843–66.PubMedCrossRef
112.
go back to reference Angell RM, Angell TD, Bamborough P, Bamford MJ, Chung CW, Cockerill SG, et al. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett. 2008;18(15):4433–7.PubMedCrossRef Angell RM, Angell TD, Bamborough P, Bamford MJ, Chung CW, Cockerill SG, et al. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett. 2008;18(15):4433–7.PubMedCrossRef
113.
go back to reference Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther. 1996;279(3):1453–61.PubMed Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther. 1996;279(3):1453–61.PubMed
114.
go back to reference Borsch-Haubold AG, Pasquet S, Watson SP. Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem. 1998;273(44):28766–72.PubMedCrossRef Borsch-Haubold AG, Pasquet S, Watson SP. Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem. 1998;273(44):28766–72.PubMedCrossRef
115.
go back to reference Goldstein DM, Gabriel T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr Top Med Chem. 2005;5(10):1017–29.PubMedCrossRef Goldstein DM, Gabriel T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr Top Med Chem. 2005;5(10):1017–29.PubMedCrossRef
116.
go back to reference Pettus LH, Wurz RP, Xu S, Herberich B, Henkle B, Liu Q, et al. Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase. J Med Chem. 2010;53(7):2973–85.PubMedCrossRef Pettus LH, Wurz RP, Xu S, Herberich B, Henkle B, Liu Q, et al. Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase. J Med Chem. 2010;53(7):2973–85.PubMedCrossRef
117.
go back to reference Nikas SN, Drosos AA. SCIO-469 Scios Inc. Curr Opin Investig Drugs. 2004;5(11):1205–12.PubMed Nikas SN, Drosos AA. SCIO-469 Scios Inc. Curr Opin Investig Drugs. 2004;5(11):1205–12.PubMed
118.
go back to reference Mavunkel BJ, Chakravarty S, Perumattam JJ, Luedtke GR, Liang X, Lim D, et al. Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue. Bioorg Med Chem Lett. 2003;13(18):3087–90.PubMedCrossRef Mavunkel BJ, Chakravarty S, Perumattam JJ, Luedtke GR, Liang X, Lim D, et al. Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue. Bioorg Med Chem Lett. 2003;13(18):3087–90.PubMedCrossRef
119.
go back to reference Genovese MC. Inhibition of p38: has the fat lady sung? Arthr Rheum. 2009;60(2):317–20.CrossRef Genovese MC. Inhibition of p38: has the fat lady sung? Arthr Rheum. 2009;60(2):317–20.CrossRef
120.
go back to reference Schieven GL. The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem. 2009;9(11):1038–48.PubMedCrossRef Schieven GL. The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem. 2009;9(11):1038–48.PubMedCrossRef
121.
go back to reference Tong SE, Daniels SE, Black P, Chang S, Protter A, Desjardins PJ. Novel p38alpha mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain. J Clin Pharmacol. 2012;52(5):717–28.PubMedCrossRef Tong SE, Daniels SE, Black P, Chang S, Protter A, Desjardins PJ. Novel p38alpha mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain. J Clin Pharmacol. 2012;52(5):717–28.PubMedCrossRef
122.
go back to reference Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003;86(6):1534–44.PubMedCrossRef Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003;86(6):1534–44.PubMedCrossRef
123.
124.
125.
go back to reference Karcher SC, Laufer SA. Successful structure-based design of recent p38 MAP kinase inhibitors. Curr Top Med Chem. 2009;9(7):655–76.PubMedCrossRef Karcher SC, Laufer SA. Successful structure-based design of recent p38 MAP kinase inhibitors. Curr Top Med Chem. 2009;9(7):655–76.PubMedCrossRef
130.
go back to reference Trejo A, Arzeno H, Browner M, Chanda S, Cheng S, Comer DD, et al. Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase. J Med Chem. 2003;46(22):4702–13.PubMedCrossRef Trejo A, Arzeno H, Browner M, Chanda S, Cheng S, Comer DD, et al. Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase. J Med Chem. 2003;46(22):4702–13.PubMedCrossRef
131.
go back to reference Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F, Emery P, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010;69(2):364–7.PubMedCrossRef Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F, Emery P, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010;69(2):364–7.PubMedCrossRef
132.
go back to reference Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, et al. p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression. J Med Chem. 2009;52(20):6257–69.PubMedCrossRef Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, et al. p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression. J Med Chem. 2009;52(20):6257–69.PubMedCrossRef
133.
go back to reference Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2012. doi:10.1002/j.1532-2149.2012.00256.x. Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2012. doi:10.​1002/​j.​1532-2149.​2012.​00256.​x.
135.
go back to reference Kim C, Cheng CY, Saldanha SA, Taylor SS. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell. 2007;130(6):1032–43.PubMedCrossRef Kim C, Cheng CY, Saldanha SA, Taylor SS. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell. 2007;130(6):1032–43.PubMedCrossRef
136.
go back to reference Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, et al. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol. 2008;9(9):1019–27.PubMedCrossRef Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, et al. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol. 2008;9(9):1019–27.PubMedCrossRef
137.
go back to reference Cheung PC, Campbell DG, Nebreda AR, Cohen P. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J. 2003;22(21):5793–805.PubMedCrossRef Cheung PC, Campbell DG, Nebreda AR, Cohen P. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J. 2003;22(21):5793–805.PubMedCrossRef
138.
go back to reference Opar A. Kinase inhibitors attract attention as oral rheumatoid arthritis drugs. Nat Rev Drug Discov. 2010;9(4):257–8.PubMedCrossRef Opar A. Kinase inhibitors attract attention as oral rheumatoid arthritis drugs. Nat Rev Drug Discov. 2010;9(4):257–8.PubMedCrossRef
139.
go back to reference Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2012;8(2):141–3.CrossRef Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2012;8(2):141–3.CrossRef
140.
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.PubMedCrossRef Hammaker D, Firestein GS. “Go upstream, young man”: lessons learned from the p38 saga. Ann Rheum Dis. 2010;69(Suppl. 1):i77–82.PubMedCrossRef
141.
go back to reference Bonilla-Hernan MG, Miranda-Carus ME, Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford). 2011;50(9):1542–50.CrossRef Bonilla-Hernan MG, Miranda-Carus ME, Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford). 2011;50(9):1542–50.CrossRef
142.
go back to reference Schieven GL, Zhang RF, Pitt S, Shen DR, Cao J, Sack J, et al. BMS-582949 is a dual action p38 kinase inhibitor well suited to avoid resistance mechanisms that increase p38 activation in cells. Arthr Rheum. 2010;62(10 Suppl.):S629–30. Schieven GL, Zhang RF, Pitt S, Shen DR, Cao J, Sack J, et al. BMS-582949 is a dual action p38 kinase inhibitor well suited to avoid resistance mechanisms that increase p38 activation in cells. Arthr Rheum. 2010;62(10 Suppl.):S629–30.
143.
go back to reference Genovese MC, Gao L, Yin J, Smith S, Weinblatt ME, Smolen JS, et al. Proof of concept study for a potent p38 MAPK dual action inhibitor BMS-582949 in subjects with RA receiving concomitant methotrexate. Arthr Rheum. 2010;62(10 Suppl.):S469–70. Genovese MC, Gao L, Yin J, Smith S, Weinblatt ME, Smolen JS, et al. Proof of concept study for a potent p38 MAPK dual action inhibitor BMS-582949 in subjects with RA receiving concomitant methotrexate. Arthr Rheum. 2010;62(10 Suppl.):S469–70.
144.
go back to reference Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov. 2009;8(6):480–99.PubMedCrossRef Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov. 2009;8(6):480–99.PubMedCrossRef
145.
go back to reference Guma M, Hammaker D, Topolewski K, Corr M, Boyle DL, Karin M, et al. Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKKk-6. Arthr Rheum. 2012;64(9):2887–95.CrossRef Guma M, Hammaker D, Topolewski K, Corr M, Boyle DL, Karin M, et al. Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKKk-6. Arthr Rheum. 2012;64(9):2887–95.CrossRef
146.
go back to reference Hammaker D, Boyle DL, Firestein GS. Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis. Rheumatology (Oxford). 2012;51(4):610–8.CrossRef Hammaker D, Boyle DL, Firestein GS. Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis. Rheumatology (Oxford). 2012;51(4):610–8.CrossRef
147.
go back to reference Engstrom W, Ward A, Moorwood K. The role of scaffold proteins in JNK signalling. Cell Prolif. 2010;43(1):56–66.PubMedCrossRef Engstrom W, Ward A, Moorwood K. The role of scaffold proteins in JNK signalling. Cell Prolif. 2010;43(1):56–66.PubMedCrossRef
148.
go back to reference Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, et al. Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem. 1997;5(1):49–64.PubMedCrossRef Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, et al. Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem. 1997;5(1):49–64.PubMedCrossRef
149.
go back to reference Liverton NJ, Butcher JW, Claiborne CF, Claremon DA, Libby BE, Nguyen KT, et al. Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem. 1999;42(12):2180–90.PubMedCrossRef Liverton NJ, Butcher JW, Claiborne CF, Claremon DA, Libby BE, Nguyen KT, et al. Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem. 1999;42(12):2180–90.PubMedCrossRef
150.
go back to reference Koeberle SC, Fischer S, Schollmeyer D, Schattel V, Grutter C, Rauh D, et al. Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase. J Med Chem. 2012;55(12):5868–77.PubMedCrossRef Koeberle SC, Fischer S, Schollmeyer D, Schattel V, Grutter C, Rauh D, et al. Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase. J Med Chem. 2012;55(12):5868–77.PubMedCrossRef
151.
go back to reference Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][ 1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38alpha MAP kinase inhibitor for the treatment of inflammatory diseases. J Med Chem. 2010;53(18):6629–39.PubMedCrossRef Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][ 1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38alpha MAP kinase inhibitor for the treatment of inflammatory diseases. J Med Chem. 2010;53(18):6629–39.PubMedCrossRef
152.
go back to reference Bode JG, Ehlting C, Haussinger D. The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis. Cell Signal. 2012;24(6):1185–94.PubMedCrossRef Bode JG, Ehlting C, Haussinger D. The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis. Cell Signal. 2012;24(6):1185–94.PubMedCrossRef
153.
go back to reference Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9(8):537–49.PubMedCrossRef Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9(8):537–49.PubMedCrossRef
Metadata
Title
Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis
Authors
Verica Paunovic
Margaret M. Harnett
Publication date
01-02-2013
Publisher
Springer International Publishing AG
Published in
Drugs / Issue 2/2013
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-013-0014-6

Other articles of this Issue 2/2013

Drugs 2/2013 Go to the issue

Adis Drug Profile

Intracameral Cefuroxime