Inhibitors for the Immuno‐ and Constitutive Proteasome: Current and Future Trends in Drug Development

Abstract

Proteolytic degradation is an essential cellular process which is primarily carried out by the 20S proteasome core particle (CP), a protease of 720 kDa and 28 individual subunits. As a result of its central functional role, the proteasome represents an attractive drug target that has been extensively investigated during the last decade and validated by the approval of bortezomib by the US Food and Drug Administration (FDA). Currently, several optimized second-generation proteasome inhibitors are being explored as anticancer drugs in clinical trials, and most of them target both constitutive proteasomes (cCPs) and immunoproteasomes (iCPs). However, selective inhibition of the iCPs, a distinct class of proteasomes predominantly expressed in immune cells, appears to be a promising therapeutic rationale for the treatment of autoimmune disorders. Although a few selective agents have already been identified, the recently determined crystal structure of the iCP will further promote the development and optimization of iCP-selective compounds.

Structural basis for dynamic regulation of the human 26S proteasome

“…The ubiquitin-proteasome pathways are essential parts of important biological processes, such as cell division, differentiation, innate immunity, adaptive immunity, regulation of gene expression, and the response to proteotoxic stress (1)(2)(3)(4). The proteasome is also an important therapeutic target in multiple myeloma (5,6).…”

Chlorocarbonylsulfenyl Chloride Cyclizations Towards Piperidin-3-yl-oxathiazol-2-ones as Potential Covalent Inhibitors of Threonine Proteases

“…Threonine proteases constitute 99 entries in the Merops database, where we specifically study the threonine-type endopeptidases, such as the proteasomes. 5 The proteasomes consist of a central proteolytic unit, known as the 20S proteasome, and the 19S regulators, which together make up a 26S structure (Figure 1). The constitutive isoform of the proteasome is expressed in all eukaryotic cells while its immunomodulatory isoform, the immunoproteasome, is mainly expressed in cells associated with the immune system, such as lymphocytes and Jukič et al: Chlorocarbonylsulfenyl Chloride Cyclizations ... monocytes.…”

“…The constitutive isoform of the proteasome is expressed in all eukaryotic cells while its immunomodulatory isoform, the immunoproteasome, is mainly expressed in cells associated with the immune system, such as lymphocytes and Jukič et al: Chlorocarbonylsulfenyl Chloride Cyclizations ... monocytes. 5,6 The constitutive proteasome contains three enzymatically active subunits, namely the b1c (caspaselike), the b2c (trypsin-like), and the β5c (chymotrypsin-like) that are embedded into a barrel-shaped structure consisting of four rings of β-subunits and α-subunits in an abbα order. The immunoproteasome has essentially the same overall structure, only the catalytically active subunits of cCP are replaced by their counterparts b1i, b2i, and β5i ( Figure 1).…”

“…[8][9][10] There is an amounting body of research on the small-molecule inhibitors of proteasomes. 5,11 Both marketed medicines, bortezomib and carfilzomib, equally inhibit the catalytically active β5 subunits of the constitutive proteasome and the immunoproteasome. The combined inhibition of both isoforms leads to cytotoxicity that limits the clinical application of these broad spectrum proteasome inhibitors.…”

“…6 In addition, many of the investigational compounds are peptide-like compounds and this represents a serious limitation to their metabolic stability and bioavailability. 5 To overcome these problems, multiple approaches can be found in literature: design of reversible proteasome inhibitors, 12 use of structural differences in the binding sites of both proteasomes in structure-based drug design, 13,14 design of highly selective and hydrolytically more stable peptidic compounds, 15 design of highly selective non-peptidic compounds, 16 use of non-catalytic residues or allosteric sites in inhibitor design, 17 and the design of selective electrophilic warheads. 18 The majority of these compounds are covalent irreversible inhibitors bearing an electrophilic warhead that is capable of reacting with the N-terminal threonine residue in the catalytic active site of the examined protease.…”