The extracellular domains of many different types of transmembrane proteins, including growth factors, growth factor receptors and cell adhesion molecules, are proteolytically released (shed) in response to environmental cues. TNF protease inhibitor 2 (TAPI-2) is a broad-spectrum inhibitor of TNF-α converting enzyme (TACE), other ADAMs (a disintegrin and metalloproteinases), and other matrix metalloproteinases. It inhibits phorbol-12-myristate-13-acetate-induced (PMA) shedding of various cell surface proteins, such as TGF-α, β amyloid precursor protein, L-selectin, and IL-6 receptor α subunit, with an IC50 value of 10 μM. TAPI-2 inhibits ADAM8, 10, 12, and TACE with Ki values of 10, 3, 100, and 0.12 μM, respectively. In T4-2 breast cancer cells, 20 μM TAPI-2 prevented mobilization of the growth factors TGF-α and amphiregulin leading to reversion of the malignant cellular phenotype.
