title: Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.
abstract: Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
authors.affiliation: Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. sandy.gould@mpi.com
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gould
authors.forename: Ruth
authors.initials: R
authors.lastname: Adams
authors.forename: Sharmila
authors.initials: S
authors.lastname: Adhikari
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Roushan
authors.initials: R
authors.lastname: Afroze
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Emily F
authors.initials: EF
authors.lastname: Calderwood
authors.forename: Ryan
authors.initials: R
authors.lastname: Chau
authors.forename: Jouhara
authors.initials: J
authors.lastname: Chouitar
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Duffey
authors.forename: Dylan B
authors.initials: DB
authors.lastname: England
authors.forename: Cheryl
authors.initials: C
authors.lastname: Farrer
authors.forename: Nancy
authors.initials: N
authors.lastname: Forsyth
authors.forename: Khristofer
authors.initials: K
authors.lastname: Garcia
authors.forename: Jeffery
authors.initials: J
authors.lastname: Gaulin
authors.forename: Paul D
authors.initials: PD
authors.lastname: Greenspan
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Harrison
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Huang
authors.forename: Natalia
authors.initials: N
authors.lastname: Iartchouk
authors.forename: Dave
authors.initials: D
authors.lastname: Janowick
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.forename: Bheemashankar
authors.initials: B
authors.lastname: Kulkarni
authors.forename: Steven P
authors.initials: SP
authors.lastname: Langston
authors.forename: Jane X
authors.initials: JX
authors.lastname: Liu
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Ma
authors.forename: Saurabh
authors.initials: S
authors.lastname: Menon
authors.forename: Hirotake
authors.initials: H
authors.lastname: Mizutani
authors.forename: Erin
authors.initials: E
authors.lastname: Paske
authors.forename: Christelle C
authors.initials: CC
authors.lastname: Renou
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Rezaei
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rowland
authors.forename: Michael D
authors.initials: MD
authors.lastname: Sintchak
authors.forename: Michael D
authors.initials: MD
authors.lastname: Smith
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Stroud
authors.forename: Ming
authors.initials: M
authors.lastname: Tregay
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Ole P
authors.initials: OP
authors.lastname: Veiby
authors.forename: Tricia J
authors.initials: TJ
authors.lastname: Vos
authors.forename: Stepan
authors.initials: S
authors.lastname: Vyskocil
authors.forename: Juliet
authors.initials: J
authors.lastname: Williams
authors.forename: Tianlin
authors.initials: T
authors.lastname: Xu
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zeng
authors.forename: Dong Mei
authors.initials: DM
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Galvin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013764:Tetrahydronaphthalenes; D048493:Proto-Oncogene Proteins B-raf