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.
|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.
|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.|
Mol Cell Proteomics 2016 Mar 28.
Delineation of molecular pathways involved in cardiomyopathies caused by troponin T mutations.
ONX-0914 purchased from AbMole
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.
|Related Proteasome Products|
|Sivelestat sodium tetrahydrate
Sivelestat sodium tetrahydrate is a competitive inhibitor of human neutrophil elastase, also inhibits leukocyte elastase obtained from rabbit, rat, hamster and mouse.
MG-101 is a potent inhibitor of cysteine proteases including calpain I (Ki = 190 nM), calpain II (Ki = 220 nM), cathepsin B (Ki = 150 nM), and cathepsin L (Ki = 500 pM). IC50 value: 150 nM (Ki)
VR23 is a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nM), chymotrypsin-like proteasomes (IC50 = 50-100 nM), and caspase-like proteasomes (IC50 = 3 μM).
Gabexate Mesylate is a serine protease inhibitor with IC50 of 0.19 μM which is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation.
CEP-18770 is an orally active inhibitor of the chymotrypsin-like activity of proteasome with IC50 of 3.8 nM, with only marginal inhibition of the tryptic and peptidylglutamyl activities of the proteosome.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.