Cell lines

The human HNSCC cell lines UMSCC-22A, UMSCC-22B, 1483, UMSCC-1, and Cal33.

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Reaction Conditions

48 h; IC50 values ranging from 58.9 to185.7 nmol/L in 8 different HNSCC cell lines.

Applications

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.

Animal models

Athymic nude mice

Dosage form

30 mg/kg; Oral taken.

Applications

Using nude mice harboring HNSCC xenograft tumors, oral administration of 30 mg/kg ONX 0912 effectively inhibited CT-L activity in normal and HNSCC tumor tissues. Treatments (10 mg/kg and 30 mg/kg) were administered via oral gavage once a day on 2 consecutive days and repeated weekly for 2 weeks. Treatment with 10 mg/kg ONX 0912 did not have a significant effect on tumor growth, relative to treatment with vehicle alone. In contrast, highly significant inhibition of HNSCC tumor growth was seen with 30 mg/kg ONX 0912 (P = 0.003). These results show that consecutive-day treatment with orally administered ONX 0912, using a dose that has previously been shown to be well tolerated, leads to inhibition of HNSCC tumor growth.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

ONX-0912 (as known as oprozomib), discovered during a medicinal chemistry effort using tripeptide epoxyketones, is an orally bio-available and potent proteasome inhibitor that inhibits growth and induces apoptosis in bortezomib resistant multiple myeloma (MM) cells. Although ONX-0912, an analog of carfilzomib, is structurally distinct from bortezomib, it possesses the same ability as bortezomib to predominantly inhibit chymotrypsin-like activity of the proteasome. ONX-0912 exhibits significant anti-MM activities to reduce tumor progression and prolong survival in many animal tumor model studies, which are associated with activation of caspase-3, caspase-8, caspase-9, and poly(ADP) ribose polymerase and inhibition of anglogensis and MM cells migration.

Reference

[1]Dharminder Chauhan, Ajita V. Singh, Monette Aujay, Christopher J. Kirk, Madhavi Bandi, Bryan Ciccarelli, Noopur Raje, Paul Richardson, and Kenneth C. Anderson. A novel oraaly active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 2010; 116(23): 4906-4915