Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Abstract

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular "machine." As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

Keywords: KDT-11; KZR-616; NFE2L1/Nrf1; RA183; RA190; RIP-1; Rpn11; Rpn13; bortezomib; capzimin; carfilzomib; immunoproteasome; ixazomib; marizomib; oprozomib; p97; proteasome; proteostasis; ubiquitin; unfolded protein response.

Figure 1

Proteasome and ubiquitin-mediated degradation [85]. (A) Schematic of substrate protein degradation by passage through the central pore of the four stacked heptameric rings that comprise the 20S proteasome (left). The X-ray crystal structure of the yeast 20S proteasome (PDB 1RYP) shows the two capping α-heptameric rings (red/violet) and the middle two β-heptamers (grey; middle). The central pore through which substrates are threaded is indicated in the top view (right). (B) The 26S proteasome is the central component of the UPS. A cartoon depiction of the components of the 26S proteasome highlights the lid and base of the 19S RP in addition to the DUB Rpn11 and the catalytic β-rings (left). The cryo-EM structure of the human 26S proteasome (PDB 6MSB) shows the structure of the 26S proteasome in a state competent for ubiquitinated substrate engagement. (C) Schematic of the ubiquitin-proteasome system (ubiquitin PDB 1UBQ). (D) Schematic of alternative 20S proteasome complexes with a heptameric PA28 cap or a monomeric PA200 cap.

Figure 2

Clinical proteasome and immunoproteasome inhibitors. Chemical structures of clinically used proteasome and immunoproteasome inhibitors. For more information, see Table 1 and Table 2.

Figure 3

Structures of non-20S UPS inhibitors. For more information, see Table 3.

Figure 4

State of proteasome inhibitors, including summary of current state and future of proteasome inhibitors [85].