PR 957
(S)-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide
CAS: 960374-59-8
Molecular Formula: C31H40N4O7
PR 957 - Names and Identifiers
PR 957 - Physico-chemical Properties
| Molecular Formula | C31H40N4O7 |
| Molar Mass | 580.67 |
| Melting Point | >70oC (dec.) |
| Solubility | DMSO 35 mg/ml mother liquor preservation: sub-package and freeze storage to avoid repeated freezing and thawing;-20 ℃,1 month;-80 ℃,6 months (after dilution, the solution temperature is low and storage may precipitate, try to use it now) Cell experiment: Dissolve with DMSO first: dilute with culture medium then, and the dilution process is recommended to be carried out in stages to avoid excessive concentration changes leading to compound precipitation. If the compound is precipitated during the dilution process, it can be redissolved by ultrasound. During dilution, ensure that the final concentration of DMSO in the working fluid should be below 0.1% as far as possible, and the maximum should not exceed 0.5%, and set up a DMSO control group with corresponding concentration. Animal experiment: Dissolve with DMSO first: dilute with water or normal saline, etc. The dilution process is recommended to be carried out in sections to avoid excessive concentration changes leading to compound p |
| Appearance | Solid |
| Color | White to Pale Yellow |
| Storage Condition | Refrigerator |
| Use | 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. |
| Target | LMP7 |
| In vitro study | ONX-0914 action on LMP7 is 20 to 40-fold more selective than action on the next most sensitive site, either β5 or LMP2. ONX-0914 inhibits lmp7-specific, MHC-I restricted antigen with minimal cross-reactivity to Constitutive proteasomes in vitro and in vivo. ONX-0914 selective inhibition of LMP7, by interferon-γ and IL-2 produced by the activated monocytes and T cells, results in inhibition of interleukin-23 (IL-23) production. Inhibition of LMP7 resulted in 90% IL-23 inhibition of production and 50% inhibition of tumor necrosis factor-α(TNF-α) and IL-6. |
| In vivo study | ONX-0914 treatment of mouse models of rheumatoid arthritis and lupus reversed signs of disease and reduced cell infiltration, cytokine production, and autoantibody levels at well tolerated doses. The maximum tolerated dose (MTD) for ONX-0914 treated mice was 30 mg/kg body weight. At the LMP7 selective concentration of ONX-0914, IFN-g release was inhibited by 60% and at higher concentrations, by 90%. ONX-0914 also inhibited IL-2 production by about 50%. |
PR 957 - Reference
| Reference Show more | 1: Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Proteasome or immunoproteasome inhibitors cause apoptosis in human renal tubular epithelial cells under normoxic and hypoxic conditions. Int Urol Nephrol. 2016 Feb 26. [Epub ahead of print] PubMed PMID: 26920131. 2: Mundt S, Basler M, Buerger S, Engler H, Groettrup M. Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice. Sci Rep. 2016 Jan 18;6:19434. doi: 10.1038/srep19434. PubMed PMID: 26776888; PubMed Central PMCID: PMC4726078. 3: Walker-Caulfield ME, Guo Y, Johnson RK, McCarthy CB, Fitz-Gibbon PD, Lucchinetti CF, Howe CL. NFκB signaling drives pro-granulocytic astroglial responses to neuromyelitis optica patient IgG. J Neuroinflammation. 2015 Sep 30;12:185. doi: 10.1186/s12974-015-0403-8. PubMed PMID: 26423139; PubMed Central PMCID: PMC4590277. 4: Howland SW, Ng GX, Chia SK, Rénia L. Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria. Parasite Immunol. 2015 Nov;37(11):599-604. doi: 10.1111/pim.12277. PubMed PMID: 26366636. 5: Zhang HM, Fu J, Hamilton R, Diaz V, Zhang Y. The mammalian target of rapamycin modulates the immunoproteasome system in the heart. J Mol Cell Cardiol. 2015 Sep;86:158-67. doi: 10.1016/j.yjmcc.2015.07.027. Epub 2015 Aug 1. PubMed PMID: 26239133. 6: Zilberberg J, Matos J, Dziopa E, Dziopa L, Yang Z, Kirk CJ, Assefnia S, Korngold R. Inhibition of the Immunoproteasome Subunit LMP7 with ONX |
PR 957 - Preparation solution concentration reference
| 1mg | 5mg | 10mg | |
|---|---|---|---|
| 1 mM | 1.722 ml | 8.611 ml | 17.221 ml |
| 5 mM | 0.344 ml | 1.722 ml | 3.444 ml |
| 10 mM | 0.172 ml | 0.861 ml | 1.722 ml |
| 5 mM | 0.034 ml | 0.172 ml | 0.344 ml |
Last Update：2024-01-02 23:10:35
PR 957 - Reference Information
| biological activity | ONX-0914 (PR-957) is an effective, selective immunoproteasome inhibitor with the lowest cross-reactivity for constitutive proteasomes in cell-free tests. |
| target | TargetValue LMP7 (Cell-free say) ~ 10 nM |
| Target | Value |
| LMP7 (Cell-free assay) | ~10 nM |
| in vitro studies | ONX-0914 acting on LMP7 is 20 to 40 times more selective than acting on the next most sensitive site β5 or LMP2. ONX-0914 inhibited LMP7-specific, MHC-I-restricted antigens in vitro and in vivo with the lowest cross-reactivity to constitutive proteasomes. ONX-0914 selective inhibition of LMP7, interferon-γ and IL-2 produced by activated monocytes and T cells, resulting in inhibition of interleukin -23(IL-23) production. Inhibition of LMP7 leads to inhibition of 90% IL-23 production, and inhibition of 50% tumor necrosis factor-α(TNF-α) and IL-6. |
| in vivo studies | ONX-0914 treat rheumatoid arthritis and lupus mouse models, reverse signs of disease, and reduce cell infiltration, cytokine production, and autoantibody levels at well-tolerated doses. The maximum tolerated dose (MTD) of ONX-0914-treated mice was 30 mg/kg body weight. When the ONX-0914 is LMP7 selective concentration, 60% IFN-g release is inhibited, and at higher concentration, 90% is inhibited. The ONX-0914 also inhibits the production of about 50% IL-2. |
Last Update：2024-04-09 20:49:11
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