product name Oprozomib (ONX 0912)
Description: Oprozomib (also known as ONX 0912 and PR 047) is a potent, orally bioavailable small molecule inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM. Oprozomibm inhibits the activity of the proteasome, thereby blocking the targeted proteolysis normally performed by the proteasome; this may result in an accumulation of unwanted or misfolded proteins. Disruption of various cell signaling pathways may follow, eventually leading to the induction of apoptosis and inhibition of tumor growth. Proteasomes are large protease complexes that degrade unneeded or damaged proteins that have been ubiquitinated
References: J Med Chem. 2009 May 14;52(9):3028-38; Blood. 2010 Dec 2;116(23):4906-15.
532.61
Formula
C25H32N4O7S
CAS No.
935888-69-0
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 100 mg/mL (187.8 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
ONX 0912 and PR 047
other peoduct :
| In Vitro |
In vitro activity: 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. Kinase 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 manufacturers 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 Assay:In trypan blue exclusion assays, ONX 0912 exhibited IC50 values ranging from 58.9 to185.7 nmol/L in 8 different HNSCC cell lines. In the 4 HNSCC cell lines (UMSCC-1, UMSCC-22B, 1483, and UMSCC-1) examined, treatment ONX 0912 resulted in processing of caspase-3 to active subunits and cleavage of the caspase substrate PARP. |
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| 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. |
| Animal model | Non-Hodgkin’s lymphoma cell line RL xenograft, colorectal tumor cell line CT-26 xenograft |
| Formulation & Dosage | Dissolved in 10% (v/v) EtOH and 10% (v/v) PS80 in citrate buffer (pH 3.5); 30 mg/kg; p.o. administration |
| References | J Med Chem. 2009 May 14;52(9):3028-38; Blood. 2010 Dec 2;116(23):4906-15. |
