Low neurotoxicity of ONX-0914 supports the idea of specific immunoproteasome inhibition as a side-effect-limiting, therapeutic strategy

Brzezinski, Laura von; Säring, Paula; Landgraf, Peter; Cammann, Clemens; Seifert, Ulrike; Dieterich, Daniela C.

doi:10.1556/1886.2017.00025

Cited by 17 publications

(11 citation statements)

References 40 publications

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“…In comparison, ONX 0914 was much more cytotoxic than YU102. This result is consistent with previous studies showing near complete cell death in a primary neuron model after 48 hours treatment with 500 nM ONX 0914 73 . In addition, we found that LPS consistently sensitizes EOC-20 microglial cells to ONX 0914 but not to YU102 (Suppl.…”

Section: Resultssupporting

confidence: 93%

A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease

Yeo

Lee

Baek

et al. 2019

Sci Rep

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The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.

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Section: Resultssupporting

confidence: 93%

A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease

Yeo

Lee

Baek

et al. 2019

Sci Rep

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“…Studies in HeLa cells have elegantly shown that at concentrations of Bortezomib leading to 75% inhibition of chymotrypsin‐like activity, which effectively induces apoptosis in sensitive myeloma cells, only small inhibition of total protein breakdown is reached . Furthermore, the number of surviving primary neurons was strongly affected in the presence of Bortezomib, whereas ONX 0914 did not affect neuronal survival at concentrations up to 0.1 μmol/L, a concentration which depletes human monocyte subsets from PBMC cultures as demonstrated in this study. Hence, different sensitivities of cells toward (immuno)proteasome inhibition probably influence the side effect profile observed with these inhibitors.…”

Section: Discussionsupporting

confidence: 47%

Inhibiting the immunoproteasome's β5i catalytic activity affects human peripheral blood‐derived immune cell viability

Pletinckx

Vaßen

Schlusche

et al. 2019

Pharmacology Res & Perspec

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Small molecule inhibitors selectively targeting the immunoproteasome subunit β5i are currently being developed for the treatment of autoimmune disorders. However, patients carrying loss‐of‐function mutations in the gene encoding β5i (Psmb8) suffer from the proteasome‐associated autoinflammatory syndromes ( PRAAS ) emphasizing the need to study pharmacological inhibition of immunoproteasome function in human cells. Here, we characterized the immunomodulatory potential of the selective β5i inhibitor ONX 0914 and Bortezomib, a pan‐proteasome inhibitor, in human peripheral blood mononuclear cells ( PBMC s). Both compounds efficiently blocked pro‐inflammatory cytokine secretion in human whole blood and PBMC cultures stimulated with toll‐like receptor ( TLR ) agonists. Furthermore, the compounds inhibited T cell cytokine production induced by recall antigen CMV pp65 or by polyclonal stimulation. The viability of PBMC s, however, was rapidly decreased in the presence of ONX 0914 and Bortezomib demonstrated by decreased residual cytosolic ATP and increased Annexin V surface binding. Interestingly, HLA ‐ DR + monocytes were rapidly depleted from the cultures in the presence of ONX 0914 as a β5i‐selective inhibitor and Bortezomib. In conclusion, the anti‐inflammatory potential of β5i‐selective inhibitors is correlating with a cytotoxicity increase in human PBMC subsets ex vivo. Our results provide important insights into the anti‐inflammatory mechanism of action of β5i‐inhibitors which currently hold the promise as a novel therapy for autoinflammatory diseases.

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“…Unlike constitutive β5 inhibitors, such as bortezomib and carfilzomib, it reduces the production of proinflammatory cytokines and cell-surface MHC Class I expression without apoptotic effects [142]. ONX0914 has shown efficacy in animal models of autoimmune disorders without affecting normal immune function [143,144]. Compared to ONX0914, KZR-616 has improved solubility and shows better efficacy in mouse models of antibody-induced arthritis [141].…”

Section: Kzr-616mentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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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.

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Low neurotoxicity of ONX-0914 supports the idea of specific immunoproteasome inhibition as a side-effect-limiting, therapeutic strategy

Cited by 17 publications

References 40 publications

A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease

A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer’s disease

Inhibiting the immunoproteasome's β5i catalytic activity affects human peripheral blood‐derived immune cell viability

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

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