Cell lines

RPMI-8226 cells

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

40 nM, 4 to 8 hours

Applications

As an inhibitor of proteasome, CEP-18770 induced an accumulation of ubiquitinated proteins over 4 to 8 hours with a profile similar to that observed after bortezomib (another proteasome inhibitor) treatment.

Animal models

SCID mice bearing human MM RPMI 8226 subcutaneous xenograft

Dosage form

Intravenous (from 1 to 6 mg/kg, 2q7d×8 injections) or oral administration (in a solution of 3% DMSO, 10% Solutol, and 87% sterile NaCl 0.9%, twice-a-week injections for 4 weeks at doses of 7.8, 10, 13 mg/kg in a volume of 20 mL/kg body weight of mouse).

Applications

Intravenous administration of CEP-18770 exhibited sustained and dose-related tumor weight inhibition with RTWI of 100% at all tested doses. CEP-18770 also exhibited dose-related increases in the incidence of tumor-free mice by the completion of the studies (120 days after tumor transplantation) within the 3- and 4-mg/kg intravenous treatment groups, 89% and 80%, respectively. Oral administration of CEP-18770 resulted in a significant reduction of tumor weight and notable dose-related incidence of complete tumor regression (75% incidence of CR and 25% tumor-free mice at 10 mg/kg orally).

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.

CEP-18770 is a novel, potent and reversible P2 threonine boronic acid inhibitor of proteasome that inhibits proteasome’s chymotrypsin-like activity, with the value of inhibition constant IC₅₀of 3.8 nM, by down-modulating the activity of nuclear factor-_KB (NF-_KB) as well as the expression of a few NF-_KB downstream effectors. Preliminary results of multiple studies have shown that CEP-18770 exerts potent antitumor activities against human multiple myeloma (MM) cell lines by inducing apoptotic cell death, exhibits a strong antiangiogenic activity suppressing RANKL-induced osteoclastogenesis, and displays a favorable cytotoxicity profile towards normal cells including epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells.

Reference

[1].Piva R, Ruggeri B, Williams M, Costa G, Tamagno I, Ferrero D, Giai V, Coscia M, Peola S, Massaia M, Pezzoni G, Allievi C, Pescalli N, Cassin M, di Giovine S, Nicoli P, de Feudis P, Strepponi I, Roato I, Ferracini R, Bussolati B, Camussi G, Jones-Bolin S, Hunter K, Zhao H, Neri A, Palumbo A, Berkers C, Ovaa H, Bernareggi A, Inghirami G. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood. 2008;111(5):2765-2775