ONX 0914 (formerly PR-957) is an immunoproteasome inhibitor with potential treatment applications in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus. ONX-0914 (PR-957) has minimal cross-reactivity for the constitutive proteasome. 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. ONX-0914 blocked progression of these diseases at well tolerated doses in preclinical models of rheumatoid arthritis and lupus. Treatment of LMP2(-/-)/MECL-1(-/-) double-deficient mice with ONX-0914 elicited a strong CTL response in lymphocytic choriomeningitis virus-infected mice.
Mol Cell Proteomics. 2016 Mar 28.
Delineation of molecular pathways involved in cardiomyopathies caused by troponin T mutations.
ONX-0914 purchased from AbMole
|Source||Mol Cell Protomics (2016). Figure 4.ONX-0914 (Cat. No. M2071, Abmole Bioscience)|
|Method||Immunoproteasome Activity Assays|
|Incubation Time||60 min|
|Results||Levels of ubiquitinated proteins in total homogenates and oxidized proteins in cytosolic homogenates (as determined using the OxyBlot procedure, which detects carbonylated proteins) were increased in I79N mice relative to WT and R278C mice, consistent with impaired UPS function.|
|Cell lines||ALL and AML cells|
|Preparation method||MTT cytotoxicity assay Cytotoxicity of bortezomib, dexamethasone, as well as their combination, and carfilzomib, ONX 0912, ONX 0914, and 5AHQ was determined using the MTT colorimetric dye reduction assay. For the drug combination study, CalcuSyn (Version 1.1.1 1996, Biosoft, Cambridge, UK) software was used to calculate a combination index (CI) based on the median-effect principle, for each drug combination tested.|
|Animal models||RIP-GP mice model|
|Formulation||an aqueous solution of 10% (wt/vol) sulfobutylether-b-cyclodextrin and 10 mM sodium citrate (pH 3.5)|
|Dosages||6 mg per kg body weight for 10 d|
|Administration||a single i.v. bolus|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
The antiviral immune response in mice devoid of immunoproteasome activity.
Basler M, et al. J Immunol. 2011 Dec 1;187(11):5548-57. PMID: 22013127.
Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells.
Ichikawa HT, et al. Arthritis Rheum. 2012 Feb;64(2):493-503. PMID: 21905015.
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