title: A new series of potent oxindole inhibitors of CDK2.
abstract: A novel series of oxindole-type inhibitors of CDK2 that have heteroatom substituted alkynyl moieties at their C-4 position is described. These novel 4-alkynyl-substituted inhibitors have superior potency relative to their parent compound in free enzyme and in cell based assays. The crystal structure of CDK2 in complex with one of these analogues was determined and gives insight to their increased potency. The biochemical evaluation of a representative derivative is also described.
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland St., Nutley, NJ 07110-1199, USA.
authors.forename: Kin-Chun
authors.initials: KC
authors.lastname: Luk
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Simcox
authors.forename: Andy
authors.initials: A
authors.lastname: Schutt
authors.forename: Karen
authors.initials: K
authors.lastname: Rowan
authors.forename: Thelma
authors.initials: T
authors.lastname: Thompson
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ursula
authors.initials: U
authors.lastname: Kammlott
authors.forename: Wanda
authors.initials: W
authors.lastname: DePinto
authors.forename: Pete
authors.initials: P
authors.lastname: Dunten
authors.forename: Apos
authors.initials: A
authors.lastname: Dermatakis
mesh_terms: D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D017239:Paclitaxel