product name ONX-0914 (PR-957)
Description: ONX-0914 (also known as PR-957) is a novel, potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay. ONX 0914 is an immunoproteasome inhibitor with potential treatment applications in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus. Preclinical studies are underway to evaluate the potential of ONX 0914 in the treatment of a range of autoimmune disorders.
References: Nat Med. 2009 Jul;15(7):781-7.
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
PR-957
other peoduct :
| 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%. Kinase Assay: 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. |
