CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib

Roberto Piva, Bruce Ruggeri, Michael Williams, Giulia Costa, Maria Tamagno, Dario Ferrero, Valentina Giai, Marta Coscia, Silvia Peola, Massimo Massaia, Gabriella Pezzoni, Cecilia Allievi, Nicoletta Pescalli, Mara Cassin, Stefano Di Giovine, Paola Nicoli, Paola De Feudis, Ivan Strepponi, Maria Roato, Riccardo FerraciniBenedetta Bussolati, Giovanni Camussi, Susan Jones-Bolin, Kathryn Hunter, Hugh Zhao, Antonino Neri, Antonio Palumbo, Celia Berkers, Huib Ovaa, Alberto Bernareggi, Giorgio Inghirami

Research output: Contribution to journalArticle

Abstract

Modulating protein ubiquitination via pro-teasome inhibition represents a promising target for cancer therapy, because of 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 that down-modulates the nuclear factor-κB (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 antiangiogenic 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.

Original languageEnglish
Pages (from-to)2765-2775
Number of pages11
JournalBlood
Volume111
Issue number5
DOIs
Publication statusPublished - Mar 1 2008

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Piva, R., Ruggeri, B., Williams, M., Costa, G., Tamagno, M., Ferrero, D., Giai, V., Coscia, M., Peola, S., Massaia, M., Pezzoni, G., Allievi, C., Pescalli, N., Cassin, M., Giovine, S. D., Nicoli, P., De Feudis, P., Strepponi, I., Roato, M., ... Inghirami, G. (2008). CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood, 111(5), 2765-2775. https://doi.org/10.1182/blood-2007-07-100651