Since the validation of anti-TNF therapy for the treatment of RA, much effort has gone into making small-molecule inhibitors that lack the cost and adverse effects associated with current large biomolecules. Researchers have actively sought out pharmacological targets that are amenable to the production of orally available drugs. One such target, TACE, was chosen because it processes membrane-bound precursor TNF to generate a soluble form of the cytokine that can act both in an autocrine manner and distally from the producing cells. The discovery of TACE permitted pharmaceutical companies to convert nonselective metalloproteinase inhibitors into selective compounds with drug-like properties. In spite of the many failures, two TACE inhibitors progressed into the clinic for treatment of RA. Unfortunately, the clinical trials were terminated in phase II because of mechanism-based hepatotoxicity and/or lack of efficacy.
Much research on the biology of TACE has been carried out since its discovery. Thought of initially as a selective enzyme that processes only precursor TNF, TACE is in fact quite promiscuous and can cleave approximately 30 membrane-spanning proteins. Clearly, inhibition of TACE might be more suitable for diseases such as cancer, in which potential drugs often have a toxicity profile that is less than ideal ( Box 1 ). In the next 10 years researchers will probably determine whether selective TACE inhibitors can stand alone as therapy for RA or other diseases such as cancer, diabetes, and cardiovascular diseases.
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We thank R Black for comments and suggestions on the manuscript.Reprint Address
Marcia L Moss, BioZyme Inc., 1513 Old White Oak Church Road, Apex, NC 27523, USA
Nat Clin Pract Rheumatol. 2008;4(6):300 © 2008
Nature Publishing Group
Cite this: Drug Insight: Tumor Necrosis Factor Converting Enzyme as a Pharmaceutical Target for Rheumatoid Arthritis - Medscape - Jun 01, 2008.