TACE and other ADAM proteases as targets for drug discovery

Tumor necrosis factor (TNF)-converting enzyme (TACE) and other ADAM proteas es (those that contain a disintegrin and a metalloprotease domain) have eme rged as potential therapeutic targets in the areas of arthritis, cancer, di abetes and HIV cachexia. TACE is the first ADAM protease to process the kno wn physiological substrate and inflammatory cytokine, membrane-bound precur sor-TNF-a, to its mature soluble form. Subsequently, TACE was shown to be r equired 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 expan ding at an exponential rate. This review focuses on TACE and other family m embers with known proteolytic function as well as the inhibitors of this cl ass of enzyme.