CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib.
Modulating protein ubiquitination via proteasome 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-kappaB (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 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.
Center for Experimental Research and Medical Studies (CeRMS) and Department of Biomedical Sciences and Human Oncology, University of Torino, Via Santena 5, Turin, Italy
Roberto
R
Piva
Bruce
B
Ruggeri
Michael
M
Williams
Giulia
G
Costa
Ilaria
I
Tamagno
Dario
D
Ferrero
Valentina
V
Giai
Marta
M
Coscia
Silvia
S
Peola
Massimo
M
Massaia
Gabriella
G
Pezzoni
Cecilia
C
Allievi
Nicoletta
N
Pescalli
Mara
M
Cassin
Stefano
S
di Giovine
Paola
P
Nicoli
Paola
P
de Feudis
Ivan
I
Strepponi
Ilaria
I
Roato
Riccardo
R
Ferracini
Benedetta
B
Bussolati
Giovanni
G
Camussi
Susan
S
Jones-Bolin
Kathryn
K
Hunter
Hugh
H
Zhao
Antonino
A
Neri
Antonio
A
Palumbo
Celia
C
Berkers
Huib
H
Ovaa
Alberto
A
Bernareggi
Giorgio
G
Inghirami
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D053245:RANK Ligand / Q000494:pharmacology; D013912:Threonine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D025801:Ubiquitin / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053245:RANK Ligand; D025801:Ubiquitin; D013912:Threonine; D000069286:Bortezomib; C527966:delanzomib; D016173:Macrophage Colony-Stimulating Factor