title: Pyrazolopyridine inhibitors of B-RafV600E. Part 2: structure-activity relationships.
abstract: Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.
authors.affiliation: ArrayBioPharma, 3200 Walnut Street, Boulder, CO 80301, United States. wenglo1056@yahoo.com
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: Kateri A
authors.initials: KA
authors.lastname: Ahrendt
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Bainian
authors.initials: B
authors.lastname: Feng
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Stefan
authors.initials: S
authors.lastname: Gradl
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hansen
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Paul
authors.initials: P
authors.lastname: Lunghofer
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: Brad
authors.initials: B
authors.lastname: Newhouse
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Jeongbeob
authors.initials: J
authors.lastname: Seo
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Sturgis
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wen
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D048493:Proto-Oncogene Proteins B-raf