CEP-18770: a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib.
Blood. 2007 Dec 5
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.
Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, owing to the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 [Cephalon] is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome which down-modulates the NF-kappaB activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong anti-angiogenic activity and potently represses RANKL - induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally-active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition. |
