title: The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase.
abstract: Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States. li.ren@arraybiopharma.com
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Kateri A
authors.initials: KA
authors.lastname: Ahrendt
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hansen
authors.forename: Brad
authors.initials: B
authors.lastname: Newhouse
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinkel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Gregg
authors.initials: G
authors.lastname: Hastings
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.forename: Kevin
authors.initials: K
authors.lastname: Rasor
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D048493:Proto-Oncogene Proteins B-raf