Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer.
The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
Dorsey
Bruce D
BD
Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. bdorsey@cephalon.com
Iqbal
Mohamed
M
Chatterjee
Sankar
S
Menta
Ernesto
E
Bernardini
Raffaella
R
Bernareggi
Alberto
A
Cassarà
Paolo G
PG
D'Arasmo
Germano
G
Ferretti
Edmondo
E
De Munari
Sergio
S
Oliva
Ambrogio
A
Pezzoni
Gabriella
G
Allievi
Cecilia
C
Strepponi
Ivan
I
Ruggeri
Bruce
B
Ator
Mark A
MA
Williams
Michael
M
Mallamo
John P
JP
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex