title: Identification of amidoheteroaryls as potent inhibitors of mutant (V600E) B-Raf kinase with in vivo activity.
abstract: A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
authors.affiliation: Cancer Research, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. paul.lyne@astrazeneca.com
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.forename: Brian
authors.initials: B
authors.lastname: Aquila
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Cook
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Jay
authors.initials: J
authors.lastname: Ezhuthachan
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
authors.forename: Timothy
authors.initials: T
authors.lastname: Pontz
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.forename: Scott
authors.initials: S
authors.lastname: Cowen
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Deegan
authors.forename: John W
authors.initials: JW
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Dominique
authors.initials: D
authors.lastname: Custeau
authors.forename: Lisa
authors.initials: L
authors.lastname: Drew
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.forename: Minhui
authors.initials: M
authors.lastname: Shen
authors.forename: Allan
authors.initials: A
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D018631:ras Proteins