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

200 Citations (Scopus)

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

Fingerprint

Proteasome Inhibitors
Tumors
Multiple Myeloma
Proteasome Endopeptidase Complex
Neoplasms
Complement Factor B
Bone
Cells
Pharmacodynamics
Ubiquitination
Chymotrypsin
Cell death
Cytotoxicity
Mesenchymal Stromal Cells
Heterografts
Osteogenesis
Intravenous Administration
Oral Administration
delanzomib
Bortezomib

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Piva, R., Ruggeri, B., Williams, M., Costa, G., Tamagno, M., Ferrero, D., ... 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

CEP-18770 : A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. / Piva, Roberto; Ruggeri, Bruce; Williams, Michael; Costa, Giulia; Tamagno, Maria; Ferrero, Dario; Giai, Valentina; Coscia, Marta; Peola, Silvia; Massaia, Massimo; Pezzoni, Gabriella; Allievi, Cecilia; Pescalli, Nicoletta; Cassin, Mara; Giovine, Stefano Di; Nicoli, Paola; De Feudis, Paola; Strepponi, Ivan; Roato, Maria; Ferracini, Riccardo; Bussolati, Benedetta; Camussi, Giovanni; Jones-Bolin, Susan; Hunter, Kathryn; Zhao, Hugh; Neri, Antonino; Palumbo, Antonio; Berkers, Celia; Ovaa, Huib; Bernareggi, Alberto; Inghirami, Giorgio.

In: Blood, Vol. 111, No. 5, 01.03.2008, p. 2765-2775.

Research output: Contribution to journalArticle

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, SD, Nicoli, P, De Feudis, P, Strepponi, I, Roato, M, 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 2008, 'CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib', Blood, vol. 111, no. 5, pp. 2765-2775. https://doi.org/10.1182/blood-2007-07-100651
Piva, Roberto ; Ruggeri, Bruce ; Williams, Michael ; Costa, Giulia ; Tamagno, Maria ; Ferrero, Dario ; Giai, Valentina ; Coscia, Marta ; Peola, Silvia ; Massaia, Massimo ; Pezzoni, Gabriella ; Allievi, Cecilia ; Pescalli, Nicoletta ; Cassin, Mara ; Giovine, Stefano Di ; Nicoli, Paola ; De Feudis, Paola ; Strepponi, Ivan ; Roato, Maria ; Ferracini, Riccardo ; Bussolati, Benedetta ; Camussi, Giovanni ; Jones-Bolin, Susan ; Hunter, Kathryn ; Zhao, Hugh ; Neri, Antonino ; Palumbo, Antonio ; Berkers, Celia ; Ovaa, Huib ; Bernareggi, Alberto ; Inghirami, Giorgio. / CEP-18770 : A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. In: Blood. 2008 ; Vol. 111, No. 5. pp. 2765-2775.
@article{253f26223b1b4fe08eec429a10d2c644,
title = "CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib",
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.",
author = "Roberto Piva and Bruce Ruggeri and Michael Williams and Giulia Costa and Maria Tamagno and Dario Ferrero and Valentina Giai and Marta Coscia and Silvia Peola and Massimo Massaia and Gabriella Pezzoni and Cecilia Allievi and Nicoletta Pescalli and Mara Cassin and Giovine, {Stefano Di} and Paola Nicoli and {De Feudis}, Paola and Ivan Strepponi and Maria Roato and Riccardo Ferracini and Benedetta Bussolati and Giovanni Camussi and Susan Jones-Bolin and Kathryn Hunter and Hugh Zhao and Antonino Neri and Antonio Palumbo and Celia Berkers and Huib Ovaa and Alberto Bernareggi and Giorgio Inghirami",
year = "2008",
month = "3",
day = "1",
doi = "10.1182/blood-2007-07-100651",
language = "English",
volume = "111",
pages = "2765--2775",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

TY - JOUR

T1 - CEP-18770

T2 - A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib

AU - Piva, Roberto

AU - Ruggeri, Bruce

AU - Williams, Michael

AU - Costa, Giulia

AU - Tamagno, Maria

AU - Ferrero, Dario

AU - Giai, Valentina

AU - Coscia, Marta

AU - Peola, Silvia

AU - Massaia, Massimo

AU - Pezzoni, Gabriella

AU - Allievi, Cecilia

AU - Pescalli, Nicoletta

AU - Cassin, Mara

AU - Giovine, Stefano Di

AU - Nicoli, Paola

AU - De Feudis, Paola

AU - Strepponi, Ivan

AU - Roato, Maria

AU - Ferracini, Riccardo

AU - Bussolati, Benedetta

AU - Camussi, Giovanni

AU - Jones-Bolin, Susan

AU - Hunter, Kathryn

AU - Zhao, Hugh

AU - Neri, Antonino

AU - Palumbo, Antonio

AU - Berkers, Celia

AU - Ovaa, Huib

AU - Bernareggi, Alberto

AU - Inghirami, Giorgio

PY - 2008/3/1

Y1 - 2008/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=41949110089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41949110089&partnerID=8YFLogxK

U2 - 10.1182/blood-2007-07-100651

DO - 10.1182/blood-2007-07-100651

M3 - Article

C2 - 18057228

AN - SCOPUS:41949110089

VL - 111

SP - 2765

EP - 2775

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -