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 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome which down-modulates the NF-κB activity and the expression of several NF-κB 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.
CEP-18770 : a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib / R. Piva, B. Ruggeri, M. Williams, G. Costa, I. Tamagno, D. Ferrero, V. Giai, M. Coscia, S. Peola, M. Massaia, G. Pezzoni, C. Allievi, N. Pescalli, M. Cassin, S. Di Giovine, P. Nicoli, P. De Feudis, I. Strepponi, I. Roato, R. Ferracini, B. Bussolati, G. Camussi, S. Jones-Bolin, K. Hunter, H. Zhao, A. Neri, A. Palumbo, C. Berkers, H. Ovaa, A. Bernareggi, G. Inghirami. - In: BLOOD. - ISSN 0006-4971. - 111:5(2008), pp. 2765-2775. [10.1182/blood-2007-07-100651]
CEP-18770 : a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib
A. Neri;
2008
Abstract
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 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome which down-modulates the NF-κB activity and the expression of several NF-κB 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.Pubblicazioni consigliate
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