Is there a future for small molecule drugs in the treatment of rheumatic diseases?

Current Opinion in Rheumatology

Volumn 20, Issue 3, 2008, Pages 257-262

  Stanczyk, Joanna ^a   Ospelt, Caroline ^a   Gay, Steffen ^a  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

Author keywords

Inflammation; Rheumatoid arthritis; Small molecule

Indexed keywords

4 [N [1 (2 CYANO 1 OXOETHYL) 4 METHYL 3 PIPERIDINYL] N METHYLAMINO]PYRROLO[2,3 D]PYRIMIDINE; 6 N (3 IODOBENZYL)ADENOSINE 5' N METHYLCARBOXAMIDE; ANTIINFLAMMATORY AGENT; APILIMOD MESYLATE; ARRY 162; ARRY 797; B7 ANTIGEN; CELL SURFACE RECEPTOR; CHEMOKINE RECEPTOR; DASATINIB; DISEASE MODIFYING ANTIRHEUMATIC DRUG; IMATINIB; INCB 18424; INTERLEUKIN 12; INTERLEUKIN 23; JANUS KINASE 3 INHIBITOR; MARAVIROC; METHOTREXATE; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; MLN 3897; NILOTINIB; PROTEIN KINASE SYK INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; R 788; RHUDEX; STA 5326; T 5224; TAMATINIB FOSDIUM; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR AP 1; UNCLASSIFIED DRUG; UNINDEXED DRUG; VX 702;

ALLERGIC ASTHMA; ARTHRITIS; BIOTECHNOLOGY; CELL ACTIVATION; CLINICAL TRIAL; CROHN DISEASE; DRUG DESIGN; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; ENTERITIS; ENZYME INHIBITION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFLAMMATION; MEDICAL RESEARCH; NONHUMAN; OUTCOME ASSESSMENT; PATIENT CARE; PRIORITY JOURNAL; PSORIASIS; PULMONARY HYPERTENSION; REVIEW; RHEUMATIC DISEASE; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SKIN FIBROSIS; SPONDYLOARTHROPATHY; SYSTEMIC SCLEROSIS;

ANTI-INFLAMMATORY AGENTS; ARTHRITIS, RHEUMATOID; HUMANS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN-TYROSINE KINASES; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 41649097975     PISSN: 10408711     EISSN: None     Source Type: Journal    
DOI: 10.1097/BOR.0b013e3282fa13ee     Document Type: Review

References (41)

1. Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861-1874. This insightful work discusses the data from clinical trials on currently available and new antirheumatic drugs. The optimized algorithms of disease assessment and potential future therapeutic targets are also presented.
2. Tarner IH, Muller-Ladner U, Gay S. Emerging targets of biologic therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 2007; 3:336-345.
3. Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease: a clinician's guide. Nat Clin Pract Rheumatol 2007; 3:651-660. A review describing the complexity and hierarchy of signal transduction in inflammatory disorders,emphasizing the latest progress in the field and translating basic molecular findings into the context of drug research.
4. Kéri G, Orfi L, Eros D, et al. Signal transduction therapy with rationally designed kinase inhibitors. Curr Signal Transduct Ther 2006; 1:67-95.
5. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004; 114:1308-1316.
6. Distler JH, Jungel A, Huber LC, et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007; 56:311-322. This is the first animal study describing the utility of tyrosine kinase inhibitor imatinib mesylate for control of dermal fibrosis. This finding may have important consequences for future therapeutic approaches in SSc.
7. Akhmetshina A, Dees C, Skhirtladse C, et al. Nilotinib and dasatinib, two novel and more potent inhibitors of c-Abl and PDGF signalling, for the treatment of experimental dermal fibrosis. In: Abstracts of the 2007. Annual Scientific Meeting of the American College of Rheumatology; Boston, MA.
8. 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.
9. Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005; 32:1650-1653.
10. Walker JG, Ahern MJ, Coleman M, et al. Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment. Ann Rheum Dis 2006; 65:1558-1564.
11. Borie DC, O'Shea JJ, Changelian PS. JAK3 inhibition, a viable new modality of immunosuppression for solid organ transplants. Trends Mol Med 2004; 10:532-541.
12. Kremer JM, Bloom BJ, Breedveld FC, et al. A randomized, double-blind, placebo-controlled trial of 3 dose levels of CP-690,550 versus placebo in the treatment of active rheumatoid arthritis. In: Program and abstracts of the American College of Rheumatology 70th Annual Meeting; 11-15 November 2006; Washington, DC.
13. Fridman J, Scherle P, Collins R, et al. Efficacy and tolerability of novel Jak inhibitors in animal models of rheumatoid arthritis. In: Abstracts of the 2007 Annual Scientific Meeting of the American College of Rheumatology; Boston, MA.
14. Navara CS. The spleen tyrosine kinase (Syk) in human disease, implications for design of tyrosine kinase inhibitor based therapy. Curr Pharm Des 2004; 10:1739-1744.
15. Cha HS, Boyle DL, Inoue T, et al. A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther 2006; 317:571-578.
16. Schett G, Zwerina J, Firestein G. The p38 mitogen activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2007. [Epub ahead of print] A comprehensive overview of p38MAPK pathway. The structure, function and biological role of p38 in inflammation and arthritis are described.
17. Mayer RJ, Callahan JF. p38 MAP kinase inhibitors: a future therapy for inflammatory diseases. Drug Discov Today Ther Strategies 2006; 3:49-54.
18. Zer C, Sachs G, Shin JM. Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factoralpha signaling. Physiol Genomics 2007; 31:343-351. This study demonstrates the limitations of targeting p38 MAPK in RA.
19. Brentano F, Kyburz D, Schorr O, et al. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005; 233:90-96.
20. Dambach D. Potential adverse effects associated with inhibition of p38alfa/beta MAP kinases. Curr Top Med Chem 2005; 5:929-939.
21. Pheneger J, Munson M, Burgess L, et al. Effects of ARRY-797, a selective, potent p38 inhibitor, in in vivo models of inflammation and arthritis. In: Abstracts of the 2007 Annual Scientific Meeting of the American College of Rheumatology; Boston, MA.
22. Koch K, Winkler J, Pheneger J, et al. Arry-162, a selective, potent Mek1/2 inhibitor, significantly reduces ex vivo IL-1 beta and TNF alpha production in normal subjects. In: Abstracts of the 2007 Annual European Congress of Rheumatology; Barcelona, Spain.
23. Yamamoto T, Aikawa Y, Hashiramoto A, et al. Characterization of antiarthritic effect of a novel small molecule AP-1 inhibitor T-5224. In: Abstracts of the 2007 Annual Scientific Meeting of the American College of Rheumatology; Boston, MA.
24. Billich A. Drug evaluation: Apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs 2007; 10:53-59.
25. Wada Y, Lu R, Zhou D, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood 2007; 109:1156-1164. This study demonstrates the inhibitory effect of STA-5326 on the Th1 cell response providing a rationale for its application in Th1-dependent autoimmune diseases.
26. Burakoff R, Barish CF, Riff D, et al. A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease. Inflamm Bowel Dis 2006; 12:558-565.
27. Madi L, Cohen S, Ochayin A, et al. Overexpression of A3 adenosine receptor in peripheral blood mononuclear cells in rheumatoid arthritis: involvement of nuclear factor-kappaB in mediating receptor level. J Rheumatol 2007; 34:20-26.
28. Bar-Yehuda S, Silverman MH, Kerns WD, et al. The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs 2007; 16:1601-1613.
29. Silverman MH, Strand V, Markovits D, et al. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial. J Rheumatol 2008; 35:41-48.
30. Tak PP. Chemokine inhibition in inflammatory arthritis. Best Pract Res Clin Rheumatol 2006; 20:929-939.
31. Emmelkamp JM, Rockstroh JK. CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions: review of the literature. Eur J Med Res 2007; 12:409-417.
32. Uvebrant K, da Graca Thrige D, Rosen A, et al. Discovery of selective small-molecule CD80 inhibitors. J Biomol Screen 2007; 12:464-472.
33. Gearing AJ. Targeting toll-like receptors for drug development: a summary of commercial approaches. Immunol Cell Biol 2007; 85:490-494. An interesting paper summarizing in a concise form TLR drug candidates including TLR agonists for application in cancer and infection and for immunomodulation in allergy, as well as TLR antagonists designed to reduce excessive inflammation.
34. Robbins M, Judge A, Liang L, et al. 2′-O-Methyl-modified RNAs act as TLR7 antagonists. Mol Ther 2007; 15:1663-1669.
35. Vanags D, Williams B, Johnson B, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial. Lancet 2006; 368:855-863.
36. Ospelt C, Gay S. Safety concerns on the development of novel therapeutic drugs. Arthritis Res Ther 2006; 8:112.
37. Hegen M, Keith JC, Jr, Collins M, Nickerson-Nutter CL. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis 2007. [Epub ahead of print] This study shows that drug efficacy observed both in AIA and CIA is more predictive of therapeutic efficacy in human RA then the data obtained from either model alone.
38. Bridges SL Jr. Personalized medicine in rheumatoid arthritis: hopes and challenges. Bull NYU Hosp Jt Dis 2007; 65:174-177.
39. Fabian MA, Biggs WH 3rd, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005; 23:329-336.
40. Muller-Ladner U, Ospelt C, Gay S, et al. Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts. Arthritis Res Ther 2007; 9:223. This work describes the distinct role of synovial fibroblasts in the pathophysiology of RA and indicates how targeted therapies may inhibit joint destructive potential of these cells.
41. Huber LC, Stanczyk J, Jungel A, Gay S. Epigenetics in inflammatory rheumatic diseases. Arthritis Rheum 2007; 56:3523-3531. This study outlines the emerging concepts of epigenetics and their application in rheumatology.