Small-molecule inhibitor: GI254023X

Name

Peptidases inhibited: Inhibits ADAM 10 with IC₅₀ = 5.3. Inhibition of ADAM 17 is 100-fold weaker (Hundhausen et al., 2003).

Synthesis: The synthese of GI254023X was first described in patents cited by Hundhausen et al. (2003), but an improved synthesis has been reported by Hoettecke et al. (2010).

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 selective inhibitor of ADAM10, GI254023X has been used in conjunction with the general inhibitor of both ADAM10 and ADAM17, GW280264X, to investigate the biological functions of the two peptidases (see Literature).