Drug Development Targeting the Ubiquitin-Proteasome System (UPS) for the Treatment of Human Cancers

Abstract

Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.

Keywords: cancer; chemoresistance; targeted therapy; ubiquitin.

Figure 1

An overview of the ubiquitin–proteasome system (UPS). UPS-mediated protein degradation requires a series of essential components: ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s) and the 26S proteasome. Within the UPS a reversed reaction of protein deubiquitylation catalyzed by deubiquitinases (DUBs) is also performed. Proteasome inhibitors targeting different components of the UPS are included (additional inhibitors targeting the 26S proteasome and the immunoproteasome are shown in Figure 3 and Figure 4, respectively).

Figure 2

UPS plays a role in regulating tumor metabolism. The UPS, especially the 26S proteasome complex, modulates both mitochondrial morphology and dynamics as well as cross-talks with the autophagy pathway.

Figure 3

Structure and inhibitors of the 26S proteasome complex. The 26S complex consists of a 20S catalytic core particle which is capped at both ends by 19S regulatory particles. Inhibitors targeting the proteasome complex are generally divided into two groups: inhibitors of 20S catalytic core particle and inhibitors of 19S regulatory particles.

Figure 4

Structure and inhibitors of the immunoproteasome complex. In immunoproteasome, β5 (PSMB5), β1 (PSMB6), and β2 (PSMB7) of the constitutive proteasome complex are replaced by their respective inducible counterparts β5i (LMP7) β1i (LMP2), and β2i (MECL-1), under inflammatory conditions and certain pathological states, including cancer. ONX-0914, PR-924 and KZR-616 are reported as selective inhibitors of immunoproteasome (Table 3).