| CAS NO: | 960374-59-8 |
| 规格: | ≥98% |
| 包装 | 价格(元) |
| 5mg | 电议 |
| 10mg | 电议 |
| 25mg | 电议 |
| 50mg | 电议 |
| 100mg | 电议 |
| 250mg | 电议 |
| 500mg | 电议 |
| Molecular Weight (MW) | 580.67 |
|---|---|
| Formula | C31H40N4O7 |
| CAS No. | 960374-59-8 |
| Storage | -20℃ for 3 years in powder form |
| -80℃ for 2 years in solvent | |
| Solubility (In vitro) | DMSO: 100 mg/mL (172.2 mM) |
| Water: <1 mg/mL | |
| Ethanol: 100 mg/mL (172.2 mM) | |
| Solubility (In vivo) | 2% DMSO+castor oil: 10 mg/mL |
| Synonyms | Synonym: ONX0914; PR-957; ONX 0914; PR 957; ONX-0914; PR957; Chemical Name: (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 InChi Key: WQAVPPWWLLVGFK-VTNASVEKSA-N InChi Code: InChI=1S/C31H40N4O7/c1-21(32-27(36)19-35-13-15-41-16-14-35)29(38)34-26(18-23-9-11-24(40-3)12-10-23)30(39)33-25(28(37)31(2)20-42-31)17-22-7-5-4-6-8-22/h4-12,21,25-26H,13-20H2,1-3H3,(H,32,36)(H,33,39)(H,34,38)/t21-,25-,26-,31+/m0/s1 SMILES Code: O=C(N[C@@H](CC1=CC=CC=C1)C([C@]2(C)OC2)=O)[C@@H](NC([C@@H](NC(CN3CCOCC3)=O)C)=O)CC4=CC=C(OC)C=C4 |
| In Vitro | In vitro activity: ONX-0914 is 20- to 40-fold more selective for LMP7 over the next most sensitive sites, β5 or LMP2. ONX-0914 blocks presentation of LMP7-specific, MHC-I–restricted antigens in vitro and in vivo with minimal cross-reactivity for the constitutive proteasome. Selective inhibition of LMP7 by ONX-0914 blocks production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. LMP7 inhibition blocks production of IL-23 by ~90% and of tumor necrosis factor-α (TNF-α) and IL-6 by ~50%. Cell Assay: 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. |
|---|---|
| In Vivo | In mouse models of rheumatoid arthritis and lupus, ONX-0914 treatment reverses signs of disease and results in reductions in cellular infiltration, cytokine production and autoantibody levels at well-tolerated doses. The maximum tolerated dose (MTD) of ONX-0914 in mice to be 30 mg/kg body weight. IFN-g release is inhibited by ~60% at LMP7-selective concentrations of ONX-0914 and by ~90% at higher concentrations. Production of IL-2 is also inhibited by ~50%. |
| Animal model | Collagen antibody–induced arthritis (CAIA) and collagen-induced arthritis (CIA) |
| Formulation & Dosage | Dissolved in 10% (w/v) sulfobutylether-β-cyclodextrin and 10 mM sodium citrate (pH 6); 2, 6 or 10 mg/kg; i.v. injection |
| References | Nat Med. 2009 Jul;15(7):781-7. |
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