A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Abstract

At the heart of the ubiquitin-proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

Keywords: autoimmune diseases; drug development; immunoproteasome; inflammation; inhibition.

Figure 1

Schematic illustration of archaeal and eukaryotic 20S proteasomes. Simple archaeal 20S proteasome core particles are built of four homo-oligomeric α- and β-rings. Being identical and harboring a catalytic Thr1 residue, all β-subunits are proteolytically active. In contrast, eukaryotic CPs bear hetero-oligomeric α- and β-rings and only three of the seven distinct β-subunits per ring, namely β1, β2 and β5, feature an active site. Note that one β2- and one β5-subunit are hidden in the back of the particle.

Figure 2

Schematic illustration of the proteasomal substrate binding channel with non-primed (S) and primed (S’) specificity pockets interacting with the amino acid side chains (P-sites) of a peptide. The proteolytically active β-subunit features the active site Thr1 and all other catalytic residues, while the neighboring β-subunits contribute specificity pockets only to the substrate binding channel and do not necessarily feature their own active site.

Figure 3

Chemical structures of non-covalently and covalently acting iCP inhibitors. Compounds are grouped and colored according to their subunit selectivity and arranged according to their discussion in the text. The original compound numbering from patents or publications was taken over wherever possible (for references see Table 1). To avoid duplicates, compounds 1a and 1b were given a letter in addition. For inhibition values see Table 1. Due to space limitations, only selected compounds of each class are depicted.