ONX-0914 (PR-957)
ONX-0914, previously known as PR-975, is a potent inhibitor of immunoproteasome, a form of proteasome generating peptides presented on major histocompatibility complex (MHC) class I molecule to cytotixic T cells, which selectively induces conformational changes in the S1 binding pocket of the immunoproteasome subunit β5i (low molecular mass polypeptide 7/LMP7) rather than the constitutive proteasome subunit β5 in human and mouse cells. ONX-0914 is able to block the production of proinflammatory cytokines from human peripheral blood mononuclear cells (PBMCs), activate mouse splenocytes, inhibit IL-17-producing T cells under TH17-polarizing cytokines in vitro, and attenuate disease progression of diabetes, arthritis, and colitis in mouse models.
Reference
Denise Niewerth, Niels E. Franke, Gerrit Jansen, Yehuda G. Assaraf, Johan van Meerloo, Christopher. Kirk, Jeremiah Degenhardt, Janet Anderl, Aaron D. Schimmer, Sonja Zweegman, Valerie de Haas, Terzah M. Horton, Gertjan J.L. Kaspers, and Jacqueline Cloos. Higer ratio immune vs. constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica 2013.
Khalid W. Kalim, Michael Basler, Christopher J. Kirk and Marcus Groettrup. Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. J Immunol 2012; 189:4182-4193
- 1. Alexander Maltsev, Sergei Funikov, et al. "Chronic Administration of Non-Constitutive Proteasome Inhibitor Modulates Long-Term Potentiation and Glutamate Signaling-Related Gene Expression in Murine Hippocampus." Int J Mol Sci. 2023 May 3;24(9):8172. PMID: 37175876
- 2. Kris Genelyn Dimasuay, Niccolette Schaunaman, et al. "Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection." Sci Rep. 2022 Aug 25;12(1):14507. PMID: 36008456
- 3. Kirby L, Jin J, et al. “Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination." Nat Commun. 2019 Aug 29;10(1):3887. PMID: 31467299
- 4. Jimenez-Guardeño JM, Apolonia L, et al. "Immunoproteasome activation enables human TRIM5α restriction of HIV-1." Nat Microbiol. 2019 Jun;4(6):933-940. PMID: 30886358
- 5. Leslie Kirby, Jing Jin, et al. "Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity." bioRxiv. 2018 November 4.
- 6. Dimasuay KG, Sanchez A, et al."Immunoproteasomes as a novel antiviral mechanism in rhinovirus-infected airways." Clin Sci (Lond). 2018 Aug 16;132(15):1711-1723. PMID: 29980604
- 7. Liu RT, Zhang P, et al. "ONX-0914, a selective inhibitor of immunoproteasome, ameliorates experimental autoimmune myasthenia gravis by modulating humoral response." J Neuroimmunol. 2017 Oct 15;311:71-78. PMID: 28844501
- 8. Ortega-Atienza S, Krawic C, et al. "20S immunoproteasomes remove formaldehyde-damaged cytoplasmic proteins suppressing caspase-independent cell death." Sci Rep. 2017 Apr 5;7(1):654. PMID: 28381880
- 9. Chen, S., et al. "Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages." Cell Death & Differentiation (2016). PMID: 26990663
| Storage | Store at -20°C |
| M.Wt | 580.67 |
| Cas No. | 960374-59-8 |
| Formula | C31H40N4O7 |
| Synonyms | ONX-0914,PR-957 |
| Solubility | ≥29.03 mg/mL in DMSO; insoluble in H2O; ≥69 mg/mL in EtOH |
| Chemical Name | (2S)-3-(4-methoxyphenyl)-N-[(2S)-1-(2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide |
| SDF | Download SDF |
| Canonical SMILES | CC(C(=O)NC(CC1=CC=C(C=C1)OC)C(=O)NC(CC2=CC=CC=C2)C(=O)C3(CO3)C)NC(=O)CN4CCOCC4 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment: [1] | |
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Cell lines |
Human peripheral blood mononuclear (PBMC)cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
200 nM, 1 hour |
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Applications |
PBMCs were treated with 200 nM ONX-0914 for 1 hour and were exposure to 1 ng/ml LPS for 24 h. Supernatants were analyzed for expression of the inflammatory cytokines. ONX-0914 selectively inhibited LMP7 (> 80%). LMP7 inhibition blocked production of IL-23 by > 90% and of tumor necrosis factor-α (TNF-α) and IL-6 by ~ 50%. Higher concentrations of ONX-0914, which induce inhibition of LMP2 and MECL-1, further decreased secretion of TNF-α and IL-6, suggesting that these subunits have a role in cytokine regulation. |
| Animal experiment: [1] | |
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Animal models |
Collagen antibody–induced arthritis (CAIA) model in BALB/c mice Collagen-induced arthritis (CIA) model in DBA1/J mice |
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Dosage form |
Intravenous injection, 2, 6 and 10 mg per kg body weight |
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Applications |
ONX-0914 blocked disease progression in a dose-dependent manner and completely ameliorated visible signs of disease at the highest dose. Inhibition of LMP7 alone was sufficient to block disease progression, as evidenced by the therapeutic response to PR-957 administered at 2 mg per kg body weight. ONX-0914 treatment also induced a rapid therapeutic response in the T and B cell–dependent CIA model. Immunoproteasome inhibition was associated with a decrease in circulating levels of autoantibodies and collagen oligomeric matrix protein (COMP), a marker for cartilage breakdown. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Muchamuel T, Basler M, Aujay M A, et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nature medicine, 2009, 15(7): 781-787. |
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| Description | ONX-0914 (PR-957) is a potent and selective inhibitor of immunoproteasome with minimal cross-reactivity for the constitutive proteasome. | |||||
| Targets | LMP7 | |||||
| IC50 | ~10 nM | |||||
Quality Control & MSDS
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