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

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

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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.

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Acknowledgements

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

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Correspondence to Marcia L Moss.

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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

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

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