Oprozomib (ONX 0912)

For research use only. Not for use in humans.

Catalog No.S7049

11 publications

Oprozomib (ONX 0912) Chemical Structure

Molecular Weight(MW): 532.61

Oprozomib (ONX 0912) is an orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM. Phase 1/2.

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10mM (1mL in DMSO) USD 310 In stock
USD 147 In stock
USD 970 In stock
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Selleck's Oprozomib (ONX 0912) has been cited by 11 publications

1 Customer Review

  • The oprozomib-mediated inhibition of 20S proteasome activity exhibits slow-binding kinetics. (A) The effect of varying concentrations of oprozomib on the relative fluorescence increase due to the 20S proteasome-catalyzed hydrolysis of Suc-LLVY-AMC. Otherwise experimental conditions and comments are as in Fig. 3A above. (B) Plot of the pseudo-first order rate constant kobs calculated from curve fitting of progress curves to an equation describing slow-binding kinetics vs. the oprozomib concentration for the oprozomib-mediated inhibition of 20S proteasome activity. The solid straight line was linear-least squares calculated and yielded an apparent second order rate constant kon of (3.8 ± 0.2) × 103 M−1·s−1 from the slope. The calculated intercept was zero within its SE, consistent with slow-binding irreversible inhibition.

    Archives of Biochemistry and Biophysics, 2018, 639:52-58. Oprozomib (ONX 0912) purchased from Selleck.

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Biological Activity

Description Oprozomib (ONX 0912) is an orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM. Phase 1/2.
Targets
20S proteasome β5 [1] 20S proteasome LMP7 [1]
36 nM 82 nM
In vitro

The anti-MM activity of Oprozomib is associated with activation of caspase-8, caspase-9, caspase-3, and PARP, as well as inhibition of migration of MM cells and angiogenesis. [2]

Assay
Methods Test Index PMID
Growth inhibition assay
Cell viability; 

PubMed: 20805366     


MM cell lines were treated with or without ONX 0912 at the indicated doses for 48 hours, followed by assessment for cell viability using MTT assays. Data presented are means ± SD (n = 3; P < .05 for all cell lines).

20805366
Western blot
Bcl-2 / Bcl-xL / Mcl-1 / Bik / Bim / Bax / Bak ; 

PubMed: 22929803     


UMSCC-22A, UMSCC-22B, 1483 and UMSCC-1 cells were treated for 24 hours with 0.1% DMSO, or 100 nmol/L carfilzomib or ONX 0912, followed by immunoblotting for the indicated proteins. In the case of Bik immunoblotting, cells were treated with 200 nmol/L carfilzomib or ONX 0912 to more clearly demonstrate Bik upregulation in 1483 and UMSCC-1 cells. Blots shown are representative of 3 independent experiments.

β-catenin / GRP94 / PERK / p-EIF2α / BiP / PDI / ATF4 ; 

PubMed: 20110419     


BCWM.1 cells were cultured with ONX0912 (2.5-100 nM) for 12 hours. Whole-cell lysates were subjected to Western blotting using anti-PARP, -caspase-9, -caspase-3, -caspase-8, -β-catenin, -GRP94, -PERK, -phosphorylated EIF2α (p-EIF2α), -BiP, -PDI, -ATF, and –β-actin antibodies.

Cyclin D1 / Cyclin D2 / Cyclin E / p21(waf1/cip1) / p27(kip1); 

PubMed: 20110419     


BCWM.1 cells were cultured with ONX0912 (10-20-50 nM) for 12 hours. Whole-cell lysates were subjected to Western blotting using anti-cyclin D1, -cyclin D2, -cyclin E, -p21 (waf1/cip1), -p27 (kip1), and -β-actin.

22929803 20110419
In vivo Oprozomib is demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It is well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response in multiple human tumor xenograft and mouse syngeneic models [1].

Protocol

Kinase Assay:[3]
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ELISA-based active site binding assay:

Samples (lysed cells or tissue homogenates) are treated for 1 h 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 min. The denatured samples are transferred to a 96-well or 384-well filter plat, mixed with streptavidin-sepharose beads (2.5-5 μL packed beads/well), and incubated for 1 h 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 diluted 1:5000 in ELISA buffer and incubated 2 h 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. For proteasome inhibitor studies, active site probe binding values are expressed as the percent of binding relative to DMSO treated cells.
Cell Research:[2]
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  • Cell lines: MM.1S, MM.1R, RPMI-8226, KMS12, INA-6, OPM-2, Dox-40
  • Concentrations: ~1 μM
  • Incubation Time: 48 h
  • Method: MTT assay
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Non-Hodgkin’s lymphoma cell line RL xenograft, colorectal tumor cell line CT-26 xenograft
  • Formulation: 10% (v/v) EtOH and 10% (v/v) PS80 in citrate buffer (pH 3.5)
  • Dosages: 30 mg/kg, twice weekly on days 1 and 2
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (187.75 mM)
Water Insoluble
Ethanol 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 Information

Molecular Weight 532.61
Formula

C25H32N4O7S

CAS No. 935888-69-0
Storage powder
in solvent
Synonyms N/A
Smiles COCC(NC(=O)C(COC)NC(=O)C1=CN=C(C)S1)C(=O)NC(CC2=CC=CC=C2)C(=O)C3(C)CO3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID