Advertisement

Intracellular signal pathways: Potential for therapies

  • Melissa Mavers
  • Eric M. Ruderman
  • Harris PerlmanEmail author
Article

Abstract

Drawbacks to current therapies for rheumatoid arthritis and the high cost of many of these drugs have lead to the investigation of novel approaches for treatment of this disease. One such tactic is the targeting of proteins involved in intracellular signal transduction. Inhibitors of p38 kinase have largely failed in clinical trials, due to both lack of efficacy and adverse events. The degree of adverse events may reflect off-target effects or, conversely, may be a mechanism-related event subsequent to successful inhibition of p38. Drugs targeting Janus kinases or spleen tyrosine kinase have shown greater success in clinical trials. A thorough analysis of specificity, as well as publication of both positive and negative results, must be the goal of continuing trials of these and other inhibitors of signal transduction molecules. The success of many clinical trials in this novel class of drugs provides optimism that more cost-effective and improved therapies will soon be available.

Keywords

Rheumatoid Arthritis Rheumatoid Arthritis Patient Mitogen Activate Protein Kinase Tace Imatinib Mesylate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Recommended Reading

  1. 1.
    Lee DM, Weinblatt ME: Rheumatoid arthritis. The Lancet 2001, 358:903–911.CrossRefGoogle Scholar
  2. 2.
    Donahue KE, Gartlehner G, Jonas DE, et al.: Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med 2008, 148:124–134.PubMedGoogle Scholar
  3. 3.
    O’Neill LAJ: Primer: Toll-like receptor signaling path-ways-what do rheumatologists need to know? Nat Clin Pract Rheum 2008, 4:319–327.CrossRefGoogle Scholar
  4. 4.
    Zhang X, Mosser DM: Macrophage activation by endogenous danger signals. J Pathol 2008, 214:161–178.PubMedCrossRefGoogle Scholar
  5. 5.
    Rincón M, Davis RJ: Regulation of the immune response by stress-activated protein kinases. Immunol Rev 2009, 228:212–224.PubMedCrossRefGoogle Scholar
  6. 6.
    Cuevas BD, Abell AN, Johnson GL: Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene 2007, 26:3159–3171.PubMedCrossRefGoogle Scholar
  7. 7.
    Schett G, Zwerina J, Firestein G: The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2008, 67:909–916.PubMedCrossRefGoogle Scholar
  8. 8.
    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. Arthritis Rheum 2009, 60:1232–1241.PubMedCrossRefGoogle Scholar
  9. 9.
    Genovese MC, Cohen SB, Wofsy D, et al.: A randomized, double-blind, placebo-controlled phase 2 study of an oral p38? MAPK inhibitor, SCIO-469, in patients with active rheumatoid arthritis [abstract 715]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  10. 10.
    Hill RJ, Dabbagh K, Phippard D, et al.: Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther 2008, 327:610–619.PubMedCrossRefGoogle Scholar
  11. 11.
    Cohen SB, Cheng T-T, Chindalore V, 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. Arthritis Rheum 2009, 60:335–344.PubMedCrossRefGoogle Scholar
  12. 12.
    Carter L, Litwiler K, Neale J, et al.: ARRY-797, a novel p38 MAP kinase inhibitor: results of a 14-day phase 1 study [abstract 359]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  13. 13.
    Lee P, Pheneger J, Brown S, et al.: ARRY-797, a selective, potent inhibitor of p38, promotes disease normalization in animal models of rheumatoid arthritis and significantly reduces ex vivo IL-1 beta, PGE2, and TNF-alpha production in normal human subjects [abstract SAT0052]. Ann Rheum Dis 2007, 66(Suppl 2):445.Google Scholar
  14. 14.
    National Institutes of Health: Clinicaltrials.gov registry. Available at http://clinicaltrials.gov. Accessed May 2009.
  15. 15.
    Kaul S, Hess H, Ji P, et al.: Anti-inflammatory effects of BMS-582949, a P38 mitogen activated protein kinase (MAPK) inhibitor, during experimental endotoxemia in healthy male subjects [abstract 354]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  16. 16.
    Wang J, Kaul S, Campanha H, et al.: Multiple ascending dose study of a potent p38 MAPK inhibitor BMS-582949 in subjects with stable RA receiving concomitant methotrexate [abstract 356]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  17. 17.
    Monahan JB, Hope H, Schindler J, et al.: Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 MAP kinase: preclinical to clinical translation [abstract FRI0001]. Presented at the European League Against Rheumatism Annual European Congress of Rheumatology. Copenhagen, Denmark; June 10–13, 2009.Google Scholar
  18. 18.
    Carter L, Brown S, Klopfenstein N, et al.: ARRY-162, a novel inhibitor of MEK kinase: phase 1A-1B pharmacokinetic and pharmacodynamic results [abstract OP-0124]. Ann Rheum Dis 2008, 67(Suppl 2):87.Google Scholar
  19. 19.
    Carter L, Brown S, Klopfenstein N, et al.: ARRY-162, a novel MEK inhibitor: results of a 14-day phase 1a study in healthy subjects and a 28-day phase 1b study in rheumatoid arthritis patients [abstract 358]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  20. 20.
    Wright AD, Pheneger J, Gomez A, et al.: ARRY-162, a potent and selective inhibitor of the MEK1/2, inhibits osteoclast differentiation and bone resorption in adjuvant-induced arthritis [abstract FRI0063]. Presented at the European League Against Rheumatism Annual European Congress of Rheumatology. Copenhagen, Denmark; June 10–13, 2009.Google Scholar
  21. 21.
    Miampamba M, Elow D, Eide L, et al.: Selective MEK1/2 inhibitors RDEA436 and RDEA119 exhibit anti-inflammatory efficacy in mono and combination therapy with methotrexate in pristane-induced arthritis in rats [abstract SAT0138]. Presented at the European League Against Rheumatism Annual European Congress of Rheumatology. Copenhagen, Denmark; June 10–13, 2009.Google Scholar
  22. 22.
    Thiel MJ, Schaefer CJ, Lesch ME, et al.: Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum 2007, 56:3347–3357.PubMedCrossRefGoogle Scholar
  23. 23.
    Murray PJ: The JAK-STAT signaling pathway: input and output integration. J Immunol 2007, 178:2623–2629.PubMedGoogle Scholar
  24. 24.
    Walker JG, Smith MD: The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005, 32:1650–1653.PubMedGoogle Scholar
  25. 25.
    Williams W, Scherle P, Shi J, et al.: A randomized placebo-controlled study of INCB018424, a selective Janus kinase 1 & 2 (JAK1&2) inhibitor in rheumatoid arthritis (RA) [abstract 714]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  26. 26.
    Jiang J-k, Ghoreschi K, Deflorian F, et al.: Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 2008, 51:8012–8018.PubMedCrossRefGoogle Scholar
  27. 27.
    West K: CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 2009, 10:491–504.PubMedGoogle Scholar
  28. 28.
    Kremer J, Cohen S, Wilkinson B, et al.: The Oral Jak inhibitor CP-690,550 (CP) in combination with methotrexate (MTX) is efficacious, safe and well tolerated in patients with active rheumatoid arthritis (RA) with an inadequate response to methotrexate alone [abstract L13]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  29. 29.
    Silverfield J, Connell C, Bloom B, et al.: CP-690,550, an oral JAK inhibitor, is a well-tolerated and effective long-term treatment for patients with moderate to severe rheumatoid arthritis [abstract 716]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  30. 30.
    Lawendy N, Krishnaswami S, Wang R, et al.: Effect of CP-690,550, an orally active Janus kinase inhibitor, on renal function in healthy adult volunteers. J Clin Pharmacol 2009, 49:423–429.PubMedCrossRefGoogle Scholar
  31. 31.
    Sada K, Takano T, Yanagi S, Yamamura H: Structure and function of Syk protein-tyrosine kinase. J Biochem 2001, 130:177–186.PubMedGoogle Scholar
  32. 32.
    Bajpai M, Chopra P, Dastidar SG, Ray A: Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis. Expert Opin Investig Drugs 2008, 17:641–659.PubMedCrossRefGoogle Scholar
  33. 33.
    Weinblatt ME, Kavanaugh A, Burgos-Vargas R, et al.: Treatment of rheumatoid arthritis with a syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum 2008, 58:3309–3318.PubMedCrossRefGoogle Scholar
  34. 34.
    Randis TM, Puri KD, Zhou H, Diacovo TG: Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 2008, 38:1215–1224.PubMedCrossRefGoogle Scholar
  35. 35.
    Camps M, Ruckle T, Ji H, et al.: Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 2005, 11:936–943.PubMedGoogle Scholar
  36. 36.
    Tohyama S, Tamura N, Haruta K, et al.: Anti-rheumatic effect of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, by inhibiting osteoclast formation [abstract 1788]. Presented at the American College of Rheumatology Annual Scientific Meeting. Boston, MA; November 6–11, 2007.Google Scholar
  37. 37.
    D’Aura Swanson C, Paniagua RT, Lindstrom TM, Robinson WH: Tyrosine kinases as targets for the treatment of rheumatoid arthritis. Nat Rev Rheumatol 2009, 5:317–324.PubMedCrossRefGoogle Scholar
  38. 38.
    Paniagua RT, Sharpe O, Ho PP, et al.: Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 2006, 116:2633–2642.PubMedGoogle Scholar
  39. 39.
    Rosengren S, Boyle DL: Imatinib inhibits synergistic effects of PDGF and TGFß on inflammatory mediator synthesis by synoviocytes and limits arthritis [abstract 2026]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  40. 40.
    Eklund KK, Joensuu H: Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases. Ann Med 2003, 35:362–367.PubMedCrossRefGoogle Scholar
  41. 41.
    Aikawa Y, Morimoto K, Yamamoto T, et al.: Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotech 2008, 26:817–823.CrossRefGoogle Scholar
  42. 42.
    Miagkov AV, Kovalenko DV, Brown CE, et al.: NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A 1998, 95:13859–13864.PubMedCrossRefGoogle Scholar
  43. 43.
    Tak PP, Gerlag DM, Aupperle KR, et al.: Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum 2001, 44:1897–1907.PubMedCrossRefGoogle Scholar
  44. 44.
    McIntyre KW, Shuster DJ, Gillooly KM, et al.: A highly selective inhibitor of IkappaB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum 2003, 48:2652–2659.PubMedCrossRefGoogle Scholar
  45. 45.
    Tas SW, Vervoordeldonk MJ, Hajji N, et al.: Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation. Arthritis Res Ther 2006, 8:R86.PubMedCrossRefGoogle Scholar
  46. 46.
    Mbalaviele G, Sommers CD, Bonar SL, et al.: A novel, highly selective, tight binding I{kappa}B kinase-2 (IKK-2) inhibitor: a tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-{kappa}B pathway in arthritis-relevant cells and animal models. J Pharmacol Exp Ther 2009, 329:14–25.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang Y, Hegen M, Xu J, et al.: Characterization of (2R, 3S)-2-( [4-(2-butynyloxy)phenyl]sulfonyl amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-[alpha] converting enzyme. Int Immunopharmacol 2004, 4:1845–1857.PubMedCrossRefGoogle Scholar
  48. 48.
    Moss ML, Sklair-Tavron L, Nudelman R: Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheum 2008, 4:300–309.CrossRefGoogle Scholar
  49. 49.
    Scatizzi JC, Mavers M, Hutcheson J, et al.: The CDK domain of p21 is a suppressor of IL-1beta-mediated inflammation in activated macrophages. Eur J Immunol 2009, 39:820–825.PubMedCrossRefGoogle Scholar
  50. 50.
    Mavers M, Balomenos D, Perlman H: The cyclin dependent kinase inhibitor p21(WAF1/CIP1) is a suppressor of inflammatory cytokine production and inflammatory arthritis [abstract 2083]. Presented at the American College of Rheumatology Annual Scientific Meeting. San Francisco, CA; October 24–29, 2008.Google Scholar
  51. 51.
    Perlman H, Pagliari LJ, Volin MV: Regulation of apoptosis and cell cycle activity in rheumatoid arthritis. Curr Mol Med 2001, 1:597–608.PubMedCrossRefGoogle Scholar
  52. 52.
    Korb A, Pavenstädt H, Pap T: Cell death in rheumatoid arthritis. Apoptosis 2009, 14:447–454.PubMedCrossRefGoogle Scholar
  53. 53.
    Kurose A, Yoshida W, Yoshida M, Sawai T: Effects of paclitaxel on cultured synovial cells from patients with rheumatoid arthritis. Cytometry 2001, 44:349–354.PubMedCrossRefGoogle Scholar
  54. 54.
    Liggins RT, Cruz T, Min W, et al.: Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits. Inflammation Res 2004, 53:363–372.CrossRefGoogle Scholar
  55. 55.
    Scatizzi JC, Hutcheson J, Perlman H: Bim-BH3 peptide mimetic therapy is effective at preventing development of inflammatory arthritis [abstract 1770]. Presented at the American College of Rheumatology Annual Scientific Meeting. Boston, MA; November 6–11, 2007.Google Scholar
  56. 56.
    Bardwell PD, Gu J, McCarthy D, et al.: The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity. J Immunol 2009, 182:7482–7489.PubMedCrossRefGoogle Scholar
  57. 57.
    Genovese MC: Inhibition of p38: has the fat lady sung? Arthritis Rheum 2009, 60:317–320.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Melissa Mavers
  • Eric M. Ruderman
  • Harris Perlman
    • 1
    Email author
  1. 1.Department of Medicine, Division of RheumatologyNorthwestern University, Feinberg School of Medicine, McGaw PavilionChicagoUSA

Personalised recommendations