Development of Proteasome Inhibitors as Therapeutic Drugs

Abstract

The proteasome is a multi-unit enzyme complex found in the cytoplasm and nucleus of all eukaryotic cells and is responsible for degradation of unneeded or damaged intracellular proteins by proteolysis, a chemical reaction that breaks peptide bonds. Proteasome inhibition presents a promising approach to cancer therapy by targeting the proteasome function in tumor cells. Delineating the success of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma, this review explores various proteasome inhibitors, currently in development, as molecular targeting agents in the fight against cancer. Proteasome inhibitors can be used alone or in combination with other conventional cancer therapies to sensitize tumor cells to cell death by various mechanisms and improve therapeutic benefits.

Figure 1. Ubiquitin-proteasome pathway and schematic of the cellular proteasome

The ubiquitin-proteasome pathway tags proteins with chains of ubiquitin to be degraded in the catalytic core of the proteasome. The ubiquitin E1 enzyme binds ubiquitin and transports it to the E2 enzyme. The E2 enzyme then transports the ubiquitin to the target substrate via the E3 ubiquitin ligase. Substrates (proteins) that are polyubiquitinated are degraded by the proteasome. Proteasomes regulate the concentration of particular proteins and degrade misfolded proteins. The proteasome is composed of the catalytic core 20S complex, which comprises α- and β-subunits, and two 19S regulatory complexes. Together with ATPases, these form the 26S proteasome. The degradation of the cellular proteins is a vital step in the regulation of various signal transduction pathways. The degradation process yields peptides which can then be further degraded into amino acids and used in synthesizing new proteins.

Figure 2. Proteasome inhibition by bortezomib

Bortezomib is a modified dipeptidyl boronic acid inhibitor that selectively and potently inhibits chymotryptic threonine protease activity, the rate-limiting proteolytic step in the proteosome. The boronic acid specifically, and with high affinity, fits the active sites (shown by stars) of the proteasome. The boronic acid group forms a complex with the threonine hydroxyl group (Thr1) in the chymotrypsin-like active site and acts as a reversible inhibitor of the chymotryptic-like activity of the proteasome, which is sufficient to inhibit proteolysis.