The 26S proteasome is a multifaceted target for anti-cancer therapies

Abstract

Proteasomes play a critical role in the fate of proteins that are involved in major cellular processes, including signal transduction, gene expression, cell cycle, replication, differentiation, immune response, cellular response to stress, etc. In contrast to non-specific degradation by lysosomes, proteasomes are highly selective and destroy only the proteins that are covalently labelled with small proteins, called ubiquitins. Importantly, many diseases, including neurodegenerative diseases and cancers, are intimately connected to the activity of proteasomes making them an important pharmacological target. Currently, the vast majority of inhibitors are aimed at blunting the proteolytic activities of proteasomes. However, recent achievements in solving structures of proteasomes at very high resolution provided opportunities to design new classes of small molecules that target other physiologically-important enzymatic activities of proteasomes, including the de-ubiquitinating one. This review attempts to catalog the information available to date about novel classes of proteasome inhibitors that may have important pharmacological ramifications.

Keywords: combined anti-cancer therapy; proteasome; proteasome inhibitors; ubiquitin-dependent proteolysis.

Figure 1. Ubiquitin-related protein degradation by proteasome

A. Shown is a scheme of the Ubiquitin Proteasome System. In general, target proteins can be covalently modified on lysine residues with one or several small (76 amino acids) proteins, called ubiquitins (Ub) (shown in red). To be transferred onto the target lysine, Ub needs to be activated first by the Ubiquitin activating enzyme (E1) by forming a thio-ester bond with the latter. This reaction requires the energy of ATP. Subsequently, Ub is transferred to one of the Ubiquitin conjugating enzymes (E2), followed by an association with a substrate-specific Ubiquitin ligase (E3) enzyme, which covalently attaches Ub to the target protein. Importantly, Ubs can modify themselves thus forming poly-Ubs chains. The target protein should be labelled by a chain of at least four Ub (poly-Ub) to be efficiently recognized by the proteasome for its subsequent degradation. B. A schematic representation of the proteasomal 19S RP. Critical subunits of the base and the lid are indicated. Rpn10 and Rnp13 ubiquitin receptor subunits are shown in orange. A substrate protein (yellow) with the ubiquitin moiety (red) is also shown. C. Shown is the schematic structure of the proteasome and small molecules (blue) that affect its different activities and the assembly. The 19S RP is shown in brown, the 20S CP comprised of alpha- and beta-type subunits (orange and green, respectively) is also presented. A substrate protein (yellow) modified with ubiquitins (red) is depicted as well as its products of degradation (yellow fragments).

Figure 2. Proteasome small molecule modulators

Chemical structures of various inhibitors of proteasomes. a. Inhibitor of PAC3 dimerization. b. Inhibitors of the 19S Regulatory particle. c. Proteasomal inhibitors studied in clinical trials.