Skip to main content

Advertisement

SpringerLink
Log in

Drug Insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis

  • Review Article
  • Published:

From Nature Clinical Practice Rheumatology

View current issue Sign up to alerts

Abstract

The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis.

Key Points

  • Biologic anti-tumor necrosis factor (TNF) agents, including etanercept, infliximab and adalimumab, reduce the severity of symptoms for individuals with rheumatoid arthritis (RA)

  • There is still an unmet medical need for orally available, small-molecule inhibitors of TNF

  • TNF-converting enzyme (TACE) has been validated in preclinical models for the treatment of RA

  • Clinical trials have not determined whether TACE inhibitors have a suitable efficacy or toxicity profile for use in patients with RA

  • TACE-selective inhibitors have been made, and could be used in the future as therapeutics

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Anti-TNF therapies and their effect on TNF signaling.
Figure 2: Structural representation of preclinical and clinical lead compounds for TACE inhibition.
Figure 3: Processing of TNFRI and TNFRII by TACE and other ADAM-family members.

Similar content being viewed by others

References

  1. Feldmann M et al. (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397–440

    Article  CAS  Google Scholar 

  2. Papadakis KA and Targan SR (2000) Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51: 289–298

    Article  CAS  Google Scholar 

  3. Hochberg MC et al. (2001) “Stepping-up” from methotrexate: a systematic review of randomised placebo controlled trials in patients with rheumatoid arthritis with an incomplete response to methotrexate. Ann Rheum Dis 60 (Suppl 3): iii51–iii54

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Voulgari PV and Drosos AA (2006) Adalimumab for rheumatoid arthritis. Expert Opin Biol Ther 6: 1349–1360

    Article  CAS  Google Scholar 

  5. Gartlehner G et al. (2006) The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 33: 2398–2408

    CAS  PubMed  Google Scholar 

  6. Jobanputra P et al. (2002) The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 6: 1–110

    Article  CAS  Google Scholar 

  7. Blumenauer B et al. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004525. 10.1002/14651858.CD004525

  8. Navarro-Sarabia F et al. Adalimumab for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD005113. 10.1002/14651858.CD005113.pub2

  9. Quinn MA et al. (2005) Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52: 27–35

    Article  CAS  Google Scholar 

  10. Geletka RC and St Clair EW (2005) Infliximab for the treatment of early rheumatoid arthritis. Expert Opin Biol Ther 5: 405–417

    Article  CAS  Google Scholar 

  11. Bongartz T et al. (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295: 2275–2285

    Article  CAS  Google Scholar 

  12. Keane J et al. (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345: 1098–1104

    Article  CAS  Google Scholar 

  13. Askling J et al. (2005) Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 64: 1414–1420

    Article  CAS  Google Scholar 

  14. Black RA et al. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385: 729–733

    Article  CAS  Google Scholar 

  15. Moss ML et al. (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385: 733–736

    Article  CAS  Google Scholar 

  16. Peschon JJ et al. (1998) An essential role for ectodomain shedding in mammalian development. Science 282: 1281–1284

    Article  CAS  Google Scholar 

  17. Conway JG et al. (2001) Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases. J Pharmacol Exp Ther 298: 900–908

    CAS  PubMed  Google Scholar 

  18. Zhang Y et al. (2004) Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S) thiomorpholinecarboxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther 309: 348–355

    Article  CAS  Google Scholar 

  19. Grootveld M and McDermott MF (2003) BMS-561392 (Bristol-Myers Squibb). Curr Opin Investig Drugs 4: 598–602

    CAS  PubMed  Google Scholar 

  20. Zhang Y et al. (2004) 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 4: 1845–1857

    Article  CAS  Google Scholar 

  21. Car B (2007) Partnering with pharmacology to probe toxicology. Presented at Society of Toxicology 46th Annual Meeting: 2007 March 25–29, Charlotte, NC

  22. Newton RC et al. (2001) Biology of TACE inhibition. Ann Rheum Dis 60 (Suppl 3): iii25–iii32

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Moss ML and Bartsch JW (2004) Therapeutic benefits from targeting of ADAM family members. Biochemistry 43: 7227–7235

    Article  CAS  Google Scholar 

  24. Dekkers PE et al. (1999) The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia. Blood 94: 2252–2258

    CAS  PubMed  Google Scholar 

  25. Li N et al. (2007) Non-cell autonomous expression of TNF-alpha-converting enzyme ADAM17 is required for normal lymphocyte development. J Immunol 178: 4214–4221

    Article  CAS  Google Scholar 

  26. Thabet MM and Huizinga TW (2006) Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs 7: 1014–1019

    CAS  PubMed  Google Scholar 

  27. Drummond AH et al. (1999) Preclinical and clinical studies of MMP inhibitors in cancer. Ann NY Acad Sci 878: 228–235

    Article  CAS  Google Scholar 

  28. Musso DL et al. (2001) N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1' isobutyl substitution. Bioorg Med Chem Lett 11: 2147–2151

    Article  CAS  Google Scholar 

  29. Lambert MH et al. (2005) Substrate specificity and novel selective inhibitors of TNF-alpha converting enzyme (TACE) from two-dimensional substrate mapping. Comb Chem High Throughput Screen 8: 327–339

    Article  CAS  Google Scholar 

  30. Rabinowitz MH et al. (2001) Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). J Med Chem 44: 4252–4267

    Article  CAS  Google Scholar 

  31. Duan JJ et al. (2002) Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships. J Med Chem 45: 4954–4957

    Article  CAS  Google Scholar 

  32. Ott GR et al. (2004) Design, synthesis and evaluation of β-benzamido hydroxamic acid inhibitors of TNF-α converting enzyme (TACE) (MEDI 324). Presented at the 228th American Chemical Society National Meeting: 2004 Aug 22–26, Philadelphia, PA

  33. Wang X et al. (2004) Inhibition of tumor necrosis factor-α converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. Mol Pharmacol 65: 890–896

    Article  CAS  Google Scholar 

  34. Duan JJ et al. (2007) Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). Bioorg Med Chem Lett 17: 266–271

    Article  CAS  Google Scholar 

  35. Lombart HG et al. (2007) Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors. Bioorg Med Chem Lett 17: 4333–4337

    Article  CAS  Google Scholar 

  36. Duan JJ et al. (2008) Discovery of β-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors. Bioorg Med Chem Lett 18: 241–246

    Article  CAS  Google Scholar 

  37. Hirata T et al. (2001) Discovery of potent, highly selective, and orally active propenohydroxamate TNF-alpha converting enzyme inhibitors (Part 1: MEDI 262 [plus poster]). Presented at the 222nd American Chemical Society National Meeting, 2001 Aug 26–30, Chicago, IL

  38. Bandarage UK et al. (2008) Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones. Bioorg Med Chem Lett 18: 44–48

    Article  CAS  Google Scholar 

  39. Sunnarborg SW et al. (2002) Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 277: 12838–12845

    Article  CAS  Google Scholar 

  40. Sahin U and Blobel CP (2007) Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17. FEBS Lett 581: 41–44

    Article  CAS  Google Scholar 

  41. Sahin U et al. (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164: 769–779

    Article  CAS  Google Scholar 

  42. Press MF and Lenz HJ (2007) EGFR, HER2 and VEGF pathways: validated targets for cancer treatment. Drugs 67: 2045–2075

    Article  CAS  Google Scholar 

  43. Kenny PA and Bissell MJ (2007) Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest 117: 337–345

    Article  CAS  Google Scholar 

  44. Horiuchi K et al. (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell 18: 176–188

    Article  CAS  Google Scholar 

  45. Zhou BB et al. (2006) Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small-cell lung cancer. Cancer Cell 10: 39–50

    Article  CAS  Google Scholar 

  46. Liu PC et al. (2006) Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells. Cancer Biol Ther 5: 657–664

    Article  CAS  Google Scholar 

  47. Schafer B et al. (2004) Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. J Biol Chem 279: 47929–47938

    Article  Google Scholar 

  48. Ohtsu H et al. (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol 291: C1–C10

    Article  CAS  Google Scholar 

  49. Lee DC et al. (2003) TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann NY Acad Sci 995: 22–38

    Article  CAS  Google Scholar 

  50. Black RA et al. (2003) Substrate specificity and inducibility of TACE (tumour necrosis factor alpha-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity. Biochem Soc Symp 70: 39–52

    Article  CAS  Google Scholar 

  51. Zimina EP et al. (2005) Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment. J Biol Chem 280: 34019–34024

    Article  CAS  Google Scholar 

  52. Li N et al. (2007) Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J 26: 494–504

    Article  CAS  Google Scholar 

  53. Horiuchi K et al. (2005) Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins β1 and β2. Dev Biol 283: 459–471

    Article  CAS  Google Scholar 

  54. Contin C et al. (2003) Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme: implications for CD40 signaling. J Biol Chem 278: 32801–32809

    Article  CAS  Google Scholar 

  55. Ahmed Z et al. (2006) TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin. FASEB J 20: 1939–1941

    Article  CAS  Google Scholar 

  56. Montero JC et al. (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16: 631–648

    Article  CAS  Google Scholar 

  57. Rabie T et al. (2005) Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V. J Biol Chem 280: 14462–14468

    Article  CAS  Google Scholar 

  58. Bergmeier W et al. (2004) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbα shedding from platelets in vitro and in vivo. Circ Res 95: 677–683

    Article  CAS  Google Scholar 

  59. Gardiner EE et al. (2007) Controlled shedding of platelet glycoprotein (GP)VI and GPIb-IX-V by ADAM family metalloproteinases. J Thromb Haemost 5: 1530–1537

    Article  CAS  Google Scholar 

  60. Zhu L et al. (2007) Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci USA 104: 1621–1626

    Article  Google Scholar 

  61. Bohm C et al. (2006) SorLA signaling by regulated intramembrane proteolysis. J Biol Chem 281: 14547–14553

    Article  Google Scholar 

  62. Hermey G et al. (2006) Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J 395: 285–293

    Article  CAS  Google Scholar 

  63. Shao MX et al. (2003) Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 100: 11618–11623

    Article  CAS  Google Scholar 

  64. Thathiah A et al. (2003) Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding. J Biol Chem 278: 3386–3394

    Article  CAS  Google Scholar 

  65. Buxbaum JD et al. (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273: 27765–27767

    Article  CAS  Google Scholar 

  66. Fabre-Lafay S et al. (2005) Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17. J Biol Chem 280: 19543–19550

    Article  CAS  Google Scholar 

  67. Zatovicova M et al. (2005) Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17. Br J Cancer 93: 1267–1276

    Article  CAS  Google Scholar 

  68. Garton KJ et al. (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 276: 37993–38001

    CAS  PubMed  Google Scholar 

  69. Qu D et al. (2007) Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. J Thromb Haemost 5: 395–402

    Article  CAS  Google Scholar 

  70. Garton KJ et al. (2003) Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem 278: 37459–37464

    Article  CAS  Google Scholar 

  71. Tsakadze NL et al. (2006) Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 281: 3157–3164

    Article  CAS  Google Scholar 

  72. Ludeman MJ et al. (2004) Regulated shedding of PAR1 N-terminal exodomain from endothelial cells. J Biol Chem 279: 18592–18599

    Article  CAS  Google Scholar 

  73. Wang Y and Sul HS (2006) Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol Cell Biol 26: 5421–5435

    Article  CAS  Google Scholar 

  74. Heller A (2006) Emerging Company Profile—Amira: Beyond Singulair. BioCentury, the Bernstein Report on BioBusiness, November 13, 2006

    Google Scholar 

Download references

Acknowledgements

We thank R Black for comments and suggestions on the manuscript.

Author information

Authors and Affiliations

  1. ML Moss is a Founder of BioZyme, Apex, NC, USA.,

    Marcia L Moss

  2. Department at Teva Pharmaceutical Industries, L Sklair-Tavron is a Project Leader and R Nudelman is a Manager in the Medicinal Chemistry, Petah Tikva, Israel.,

    Liora Sklair-Tavron & Raphael Nudelman

Authors
  1. Marcia L Moss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liora Sklair-Tavron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raphael Nudelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcia L Moss.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moss, M., Sklair-Tavron, L. & Nudelman, R. Drug Insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Rev Rheumatol 4, 300–309 (2008). https://doi.org/10.1038/ncprheum0797

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0797

  • Springer Nature Limited

This article is cited by

Search

Navigation