title: Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer.
abstract: 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.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. bdorsey@cephalon.com
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Mohamed
authors.initials: M
authors.lastname: Iqbal
authors.forename: Sankar
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Ernesto
authors.initials: E
authors.lastname: Menta
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bernardini
authors.forename: Alberto
authors.initials: A
authors.lastname: Bernareggi
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Cassarà
authors.forename: Germano
authors.initials: G
authors.lastname: D'Arasmo
authors.forename: Edmondo
authors.initials: E
authors.lastname: Ferretti
authors.forename: Sergio
authors.initials: S
authors.lastname: De Munari
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Oliva
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pezzoni
authors.forename: Cecilia
authors.initials: C
authors.lastname: Allievi
authors.forename: Ivan
authors.initials: I
authors.lastname: Strepponi
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: John P
authors.initials: JP
authors.lastname: Mallamo
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex