title: Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase.
abstract: This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. Electronic address: bnewhouse@arraybiopharma.com.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Newhouse
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Walter C
authors.initials: WC
authors.lastname: Voegtli
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Kateri
authors.initials: K
authors.lastname: Ahrendt
authors.forename: Alex
authors.initials: A
authors.lastname: Buckmelter
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Nathalie
authors.initials: N
authors.lastname: Klopfenstein
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wen
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.forename: Bainian
authors.initials: B
authors.lastname: Feng
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D011687:Purines; C064191:1H-imidazo(4,5-b)pyridine; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; DFG-in; Imidazopyridine; Scaffold hopping; αC-helix out