Small-molecule inhibitor: GW280264X

Name

Peptidases inhibited: GW280264X is a potent inhibitor of both ADAM 10 (IC₅₀ = 11.5 nM) and ADAM 17 (IC₅₀ = 8.0) (Hundhausen et al. (2003)).

Synthesis: Patents describing the synthesis of GW280264X are cited by Hundhausen et al. (2003).

Inhibitor class: This compound contains functionality of the hydroxamate class of metallopeptidase inhibitors. The first full report of hydroxamates as metallopeptidase inhibitors was that of Nishino & Powers (1978). These are reversible inhibitors in which the hydroxamic acid group forms a bidentate complex with the active site zinc. A structure (Holmes & Matthews, 1981) showed both the carbonyl oxygen and the hydroxyl oxygen close to the zinc. Specificity is achieved by fitting of other parts of the molecules to prime-side substrate-binding sites. An excellent early review of the hydroxamates as metallopeptidase inhibitors was that of Powers & Harper (1986) (pp. 244-253).
Comment: As a potent inhibitor of both ADAM10 and ADAM17, GW280264X has been used in conjunction with the selective inhibitor of ADAM10, GI254023X, to investigate the biological functions of the two peptidases (see Literature).