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Abstract
A structure-based virtual screening of over 400,000 small molecules against the constitutive proteasome activity followed by in vitro assays led to the discovery of a family of proteasome inhibitors with a sulfonyl piperazine scaffold. Some members of this family of small non-peptidic inhibitors were found to act selectively on the β2 trypsin-like catalytic site with a preference for the immunoproteasome β2i over the constitutive proteasome β2c, while some act on the β5 site and post-acid site β1 of both, the immunoproteasome and the constitutive proteasome. Anti-proliferative and anti-invasive effects on tumor cells were investigated and observed for two compounds. We report novel chemical inhibitors able to interfere with the three types of active centers of both, the immuno- and constitutive proteasomes. Identifying and analyzing a novel scaffold with decorations able to shift the binders’ active site selectivity is essential to design a future generation of proteasome inhibitors able to distinguish the immunoproteasome from the constitutive proteasome.
Highlights
The constitutive ubiquitin-proteasome system is mainly implicated in the controlled degradation of proteins in eukaryotic cells [1]
Identifying and analyzing a novel scaffold with decorations able to shift the binders’ active site selectivity is essential to design a future generation of proteasome inhibitors able to distinguish the immunoproteasome from the constitutive proteasome
Since an increased degradation by proteasome of cell cycle inhibitors or proapoptotic proteins contributes to malignant transformation [2, 3], considerable efforts to develop proteasome inhibitors were made and led to three approved drugs, bortezomib for the treatment of multiple myeloma [4] and mantle lymphoma [5], carfilzomib [6] and the orally available ixazomib [7] for the treatment of multiple myeloma (Figure 1A)
Summary
The constitutive ubiquitin-proteasome system is mainly implicated in the controlled degradation of proteins in eukaryotic cells [1]. Since an increased degradation by proteasome of cell cycle inhibitors or proapoptotic proteins contributes to malignant transformation [2, 3], considerable efforts to develop proteasome inhibitors were made and led to three approved drugs, bortezomib for the treatment of multiple myeloma [4] and mantle lymphoma [5], carfilzomib [6] and the orally available ixazomib [7] for the treatment of multiple myeloma (Figure 1A) These covalent inhibitors inhibit mainly the β5 activity of the catalytic core of the constitutive proteasome (cCP) and, indiscriminately, that of the catalytic core of the immunoproteasome (iCP). The reversible binding provides enzymeinhibitor complexes with a limited life-time and favors inhibitor widespread tissue distribution [10]
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