TACE and other ADAM proteases as targets for drug discovery

Tumor necrosis factor (TNF)-converting enzyme (TACE) and other ADAM proteases (those that contain a disintegrin and a metalloprotease domain) have emerged as potential therapeutic targets in the areas of arthritis, cancer, diabetes and HIV cachexia. TACE is the first ADAM protease to process the known physiological substrate and inflammatory cytokine, membrane-bound precursor-TNF-alpha, to its mature soluble form. Subsequently, TACE was shown to be required for several different processing events such as tumor growth factor-alpha (TGF-alpha) precursor and amyloid precursor protein (APP) cleavage. With the recent discoveries of the proteolytic specificities of other ADAM family members, the information surrounding these metalloproteases is expanding at an exponential rate. This review focuses on TACE and other family members with known proteolytic function as well as the inhibitors of this class of enzyme.