Small-molecule inhibitor: MG-262

Name

Common name: MG-262
Other names: proteasome inhibitor III; proteasome inhibitor 3; PSI-III; PSI-3

History: Early reports of the effectiveness of peptidyl boronic acids as inhibitors of the peptidase activities of the proteasome were those of McCormack et al. (1997) and Adams et al. (1998). These studies showed that sub-nanomolar K_i values were possible.
Peptidases inhibited: Inhibits primarily the chymotrypsin-like activity of the proteasome that is due to catalytic subunit 3. Also inhibits Lon-A peptidase with IC₅₀ 122 nM (Frase et al., 2006). Inhibition of calpains and cathepsins has also been detected.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Inhibitors of the peptidase activities of the proteasome are of interest in connection for cancer chemotherapy and other indications. The peptidic nature of MG-262 is likely to make it less stable in vivo than non-peptidic analogues.

Inhibitor class: This compound is of the class of boron-containing inhibitors of protein-nucleophile peptidases. Such compounds were first described by Antonov et al. (1970) and Philipp & Bender (1971). They usually interact with the hydroxyl of serine or threonine in the enzyme active site to form a tetrahedral adduct that is structurally related to the tetrahedral intermediate in substrate hydrolysis.
Comment: This cell-permeant peptide boronic acid is structurally similar to the peptide aldehyde MG132, but inhibits the chymotrypsin-like peptidase activity of the proteasome with much higher potency.