ONX-0914 (PR-957)

Catalog No.S7172

ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.

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ONX-0914 (PR-957) Chemical Structure

ONX-0914 (PR-957) Chemical Structure
Molecular Weight: 580.67

Validation & Quality Control

Quality Control & MSDS

Proteasome Inhibitors with Unique Features

  • Pan Proteasome Inhibitor

    Ixazomib (MLN2238) β5 site, IC50=3.4 nM; β1 site, IC50=31 nM; β2 site, IC50=3500 nM.

  • Most Potent Proteasome Inhibitor

    Bortezomib (PS-341) 20S proteasome, Ki of 0.6 nM.

  • FDA-approved Proteasome Inhibitor

    Carfilzomib (PR-171) Approved by FDA for multiple myeloma.

  • Newest Proteasome Inhibitor

    Oprozomib (ONX 0912) Orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM.

Product Information

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  • Research Area

Product Description

Biological Activity

Description ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.
Targets LMP7 [1]
(Cell-free assay)
IC50 ~10 nM
In vitro 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%.[1]
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%.[1]
Features The first highly selective, small molecule inhibitor of the immunoproteasome. Potential use in cancer and autoimmune diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, and lupus).

Protocol(Only for Reference)

Kinase Assay: [1]

Proteasome active site ELISA Briefly, samples (lysed cells or tissue homogenates) are treated for 1 hr at room temperature with the biotinylated active site probe PR-584 (5-15 μM). Samples are denatured by addition of SDS (0.9% final) and heating to 100°C for 5 minutes. The denatured samples are transferred to a 96-well or 384-well filter plate, mixed with streptavidin-sepharose beads (2.5-5 μL packed beads/well), and incubated for 1 hour at room temperature on a plate shaker. The beads are washed 5 times with 100-200 μL/well of ELISA buffer (PBS, 1% bovine serum albumin, 0.1% Tween-20) by vacuum filtration. The beads are incubated overnight at 4°C on a plate shaker with the following antibodies recognizing the six catalytic subunits diluted into ELISA buffer: β5, β1, and β2 diluted 1:3000; LMP7 and LMP2 diluted 1:5000; and MECL-1 diluted 1:1000. The beads are washed 5 times with 100-200 μL/well of ELISA buffer and incubated with HRP-conjugated secondary antibody (goat anti-rabbit for β5, rabbit anti-goat for MECL-1, and goat anti-mouse for LMP7, LMP2, β1 and β2) diluted 1:5000 in ELISA buffer and incubated 2 hours at room temperature on a plate shaker. The beads are washed 5 times with 100-200 μL/well of ELISA buffer and developed for chemiluminsecence signal using the supersignal ELISA pico substrate following the manufacturer's instructions. Luminescence is measured on a plate reader and converted to ng of proteasome or μg/mL of lysate by comparison with 20S proteasome or untreated cell lysate standard curves.

Animal Study: [1]

Animal Models collagen antibody–induced arthritis (CAIA) and collagen-induced arthritis (CIA)
Formulation 10% (w/v) sulfobutylether-β-cyclodextrin and 10 mM sodium citrate (pH 6)
Dosages 2, 6 or 10 mg/kg
Administration i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Muchamuel T, et al. Nat Med, 2009, 15(7), 781-787.

Chemical Information

Download ONX-0914 (PR-957) SDF
Molecular Weight (MW) 580.67
Formula

C31H40N4O7

CAS No. 960374-59-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 100 mg/mL (172.21 mM)
Ethanol 100 mg/mL (172.21 mM)
Water <1 mg/mL (<1 mM)
In vivo 2% DMSO+castor oil 10 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name L-Tyrosinamide, N-[2-(4-morpholinyl)acetyl]-L-alanyl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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