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.
Piva
Roberto
R
Center for Experimental Research and Medical Studies (CeRMS) and Department of Biomedical Sciences and Human Oncology, University of Torino, Via Santena 5, Turin, Italy
Ruggeri
Bruce
B
Williams
Michael
M
Costa
Giulia
G
Tamagno
Ilaria
I
Ferrero
Dario
D
Giai
Valentina
V
Coscia
Marta
M
Peola
Silvia
S
Massaia
Massimo
M
Pezzoni
Gabriella
G
Allievi
Cecilia
C
Pescalli
Nicoletta
N
Cassin
Mara
M
di Giovine
Stefano
S
Nicoli
Paola
P
de Feudis
Paola
P
Strepponi
Ivan
I
Roato
Ilaria
I
Ferracini
Riccardo
R
Bussolati
Benedetta
B
Camussi
Giovanni
G
Jones-Bolin
Susan
S
Hunter
Kathryn
K
Zhao
Hugh
H
Neri
Antonino
A
Palumbo
Antonio
A
Berkers
Celia
C
Ovaa
Huib
H
Bernareggi
Alberto
A
Inghirami
Giorgio
G
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