ONX-0914 - CAS 960374-59-8
Catalog number:
Not Intended for Therapeutic Use. For research use only.
ONX 0914 is an immunoproteasome inhibitor with potential treatment applications in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus. ONX 0914 was designed to be a potent inhibitor of the immunoproteasome with minimal cross-reactivity for the constitutive proteasome. Recent evidence suggests that the immunoproteasome regulates the production of several inflammatory cytokines, including Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), IL-17, and IL-23. In preclinical models of rhematoid arthritis and lupus, ONX 0914 blocked progression of these diseases at well-tolerated doses. Preclinical studies are underway to evaluate the potential of ONX 0914 in the treatment of a range of autoimmune disorders.
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white to off-white solid powder
ONX 0914; ONX0914; PR-957; PR957; PR 957.
Current Developer:
Onyx Pharmaceuticals.
1.Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines.
Niewerth D, Kaspers GJ, Assaraf YG, van Meerloo J, Kirk CJ, Anderl J, Blank JL, van de Ven PM, Zweegman S, Jansen G, Cloos J1. J Hematol Oncol. 2014 Jan 13;7:7. doi: 10.1186/1756-8722-7-7.
BACKGROUND: Despite encouraging results with the proteasome inhibitor bortezomib in the treatment of hematologic malignancies, emergence of resistance can limit its efficacy, hence calling for novel strategies to overcome bortezomib-resistance. We previously showed that bortezomib-resistant human leukemia cell lines expressed significantly lower levels of immunoproteasome at the expense of constitutive proteasomes, which harbored point mutations in exon 2 of the PSMB5 gene encoding the β5 subunit. Here we investigated whether up-regulation of immunoproteasomes by exposure to interferon-γ restores sensitivity to bortezomib in myeloma and leukemia cell lines with acquired resistance to bortezomib.
2.Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria.
Howland SW1, Ng GX1,2, Chia SK1,3, Rénia L1,2,3. Parasite Immunol. 2015 Nov;37(11):599-604. doi: 10.1111/pim.12277.
Aside from antimalarials, there is currently no treatment for cerebral malaria, a fulminant neurological complication of P. falciparum infection that is a leading cause of death in African children. In the mouse model of cerebral malaria, cross-presentation of parasite antigens by brain endothelial cells is thought to be a crucial late step in pathogenesis. We have investigated three proteasome inhibitors as potential adjunct therapies: bortezomib, carfilzomib and ONX-0914. Only carfilzomib, an irreversible inhibitor of both constitutive proteasomes and immunoproteasomes, was able to inhibit cross-presentation of malaria antigen by murine brain endothelial cells in vitro. To mimic the clinical setting, carfilzomib was co-administered with artesunate only when infected mice exhibited neurological defects. However, there was no improvement in survival compared to artesunate monotherapy. The treatment failure was explained by the inability of daily or twice daily bolus doses of carfilzomib to inhibit cross-presentation by brain endothelial cells in vivo.
3.Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model.
Zilberberg J1, Matos J2, Dziopa E2, Dziopa L2, Yang Z2, Kirk CJ3, Assefnia S4, Korngold R2. Biol Blood Marrow Transplant. 2015 Sep;21(9):1555-64. doi: 10.1016/j.bbmt.2015.06.010. Epub 2015 Jun 18.
In the current study we evaluated the effects of immunoproteasome inhibition using ONX 0914 (formerly PR-957) to ameliorate graft-versus-host disease (GVHD). ONX 0914, an LMP7-selective epoxyketone inhibitor of the immunoproteasome, has been shown to reduce cytokine production in activated monocytes and T cells and attenuate disease progression in mouse models of rheumatoid arthritis, colitis, systemic lupus erythematosus, and, more recently, encephalomyelitis. Inhibition of LMP7 with ONX 0914 in the B10.BR→CBA MHC-matched/minor histocompatibility antigen (miHA)-disparate murine blood and marrow transplant (BMT) model caused a modest but significant improvement in the survival of mice experiencing GVHD. Concomitant with these results, in vitro mixed lymphocyte cultures revealed that stimulator splenocytes, but not responder T cells, treated with ONX 0914 resulted in decreased IFN-γ production by allogeneic T cells in both MHC-disparate (B10.
4.Differential global structural changes in the core particle of yeast and mouse proteasome induced by ligand binding.
Arciniega M1, Beck P2, Lange OF3, Groll M2, Huber R4. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9479-84. doi: 10.1073/pnas.1408018111. Epub 2014 Jun 16.
Two clusters of configurations of the main proteolytic subunit β5 were identified by principal component analysis of crystal structures of the yeast proteasome core particle (yCP). The apo-cluster encompasses unliganded species and complexes with nonpeptidic ligands, and the pep-cluster comprises complexes with peptidic ligands. The murine constitutive CP structures conform to the yeast system, with the apo-form settled in the apo-cluster and the PR-957 (a peptidic ligand) complex in the pep-cluster. In striking contrast, the murine immune CP classifies into the pep-cluster in both the apo and the PR-957-liganded species. The two clusters differ essentially by multiple small structural changes and a domain motion enabling enclosure of the peptidic ligand and formation of specific hydrogen bonds in the pep-cluster. The immune CP species is in optimal peptide binding configuration also in its apo form. This favors productive ligand binding and may help to explain the generally increased functional activity of the immunoproteasome.
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