Immunoproteasome inhibition and bioactivity of thiasyrbactins

Abstract

A family of macrodilactam natural products, the syrbactins, are known proteasome inhibitors. A small group of syrbactin analogs was prepared with a sulfur-for-carbon substitution to enhance synthetic accessibility and facilitate modulation of their solubility. Two of these compounds surprisingly proved to be inhibitors of the trypsin-like catalytic site, including of the immunoproteasome. Their bound and free conformations suggest special properties of the thiasyrbactin ring are responsible for this unusual preference, which may be exploited to develop drug-like immunoproteasome inhibitors. These compounds show greater selectivity than earlier compounds used to infer phenotypes of immunoproteasome inhibition, like ONX-0914.

Thiasyrbactins Induce Cell Death via Proteasome Inhibition in Multiple Myeloma Cells

“…NAM compounds have been shown to inhibit the T-L subunit of the immunoproteasome. As these compounds had moderate biological activities against NB cells (30), we here tested the effects of these compounds on four hematologic cell lines of plasma immune cells. In cell viability assessments, the EC50 values for NAM-93 and NAM-105 were <2.08 μM across all MM cell lines with sub-micromolar concentrations for NAM-93.…”

“…demonstrated the extent of constitutive proteasome and immunoproteasome inhibition by thiasyrbactins (NAMs) using an in vitro-based proteasomal activity assay. The tested NAM compounds predominantly inhibited the CT-L and T-L activities of the constitutive proteasome, but potently and selectively inhibited the T-L activity of the immunoproteasome, with little effect on the CT-L and C-L sub-catalytic sites (30).…”

“…NAM-93 and NAM-95 were specifically designed to improve solubility. Recently, we reported that these thiasyrbactins preferentially inhibited the T-L (β2i) subunit of the immunoproteasome using an in vitro proteasomal activity assay that relies on purified immunoproteasomes (30). In this paper, we present evidence that these thiasyrbactins pass the cell membrane and induce cell death of actively dividing MM cells via inhibition of the proteasome.…”

Natural product scaffolds as inspiration for the design and synthesis of 20S human proteasome inhibitors

“…These analogues were reported for their activity towards both the constitutive and immunoproteasomes, more selectively inhibiting the T-L site of the immunoproteasome. 79 The biological activity of the analogues was further examined through cytotoxicity experiments with numerous neuroblastoma cell lines. The thiasyrbactin scaffold has established itself as a drug-like starting point for inhibition of the immunoproteasome.…”

Argyrin B, a non‐competitive inhibitor of the human immunoproteasome exhibiting preference for β1i

“…Most existing proteasome inhibitors block the active sites of both the constitutive proteasome and immunoproteasome at similar potencies (Bakas et al., ; Kuhn & Orlowski, ; Parlati et al., ). However, significant advancements in crystal structure elucidations have enabled the identification of sufficient structural differences in the binding pockets of the different forms of proteasomes (Groll, Berkers, Ploegh, & Ovaa, ; Harshbarger, Miller, Diedrich, & Sacchettini, ; Huber et al., ; Santos et al., ) to allow for selective structure‐based drug design and selective inhibition.…”