ADAM metallopeptidase domain 17 (ADAM17) (ADAM17)

ADAM metallopeptidase domain 17 (ADAM17), also widely known as TNF-alpha converting enzyme (TACE), is a membrane-anchored metalloprotease and a critical member of the 'A Disintegrin And Metalloproteinase' family [5, 9, 12]. It is the primary enzyme responsible for the 'ectodomain shedding' of various cell-surface proteins, most notably converting the membrane-bound precursor of TNF-alpha into its active, soluble systemic form [1, 7]. Beyond its role in inflammation, ADAM17 processes more than 80 other substrates, including epidermal growth factor receptor (EGFR) ligands and Notch receptors, which are essential for cell growth and survival signaling [2, 4, 11]. Due to its central regulatory function in immune responses and oncogenesis, it has been targeted for the treatment of chronic inflammatory conditions such as rheumatoid arthritis and Crohn's disease, as well as several types of cancer [10, 13, 16]. However, early development of small-molecule inhibitors was hindered by a lack of selectivity leading to significant liver and musculoskeletal toxicities [4, 8, 13]. More recent drug development efforts have focused on monoclonal antibodies and allosteric inhibitors to achieve the necessary specificity required for therapeutic safety [1, 2, 4].

Other names

TNF-alpha converting enzymeTACETumor necrosis factor-alpha converting enzymeCD156bA disintegrin and metalloproteinase domain 17CSVPCD156q

Inhibition of the proteolytic cleavage (shedding) of membrane-bound precursors, such as pro-TNF-alpha and EGFR ligands, into their soluble active forms, thereby reducing pro-inflammatory and pro-proliferative signaling.