title: Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.
abstract: Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.
authors.affiliation: GlaxoSmithKline Inc., Five Moore Drive, Research Triangle Park, North Carolina 27709, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Bramson
authors.forename: J
authors.initials: J
authors.lastname: Corona
authors.forename: S T
authors.initials: ST
authors.lastname: Davis
authors.forename: S H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: M
authors.initials: M
authors.lastname: Edelstein
authors.forename: S V
authors.initials: SV
authors.lastname: Frye
authors.forename: R T
authors.initials: RT
authors.lastname: Gampe
authors.forename: P A
authors.initials: PA
authors.lastname: Harris
authors.forename: A
authors.initials: A
authors.lastname: Hassell
authors.forename: W D
authors.initials: WD
authors.lastname: Holmes
authors.forename: R N
authors.initials: RN
authors.lastname: Hunter
authors.forename: K E
authors.initials: KE
authors.lastname: Lackey
authors.forename: B
authors.initials: B
authors.lastname: Lovejoy
authors.forename: M J
authors.initials: MJ
authors.lastname: Luzzio
authors.forename: V
authors.initials: V
authors.lastname: Montana
authors.forename: W J
authors.initials: WJ
authors.lastname: Rocque
authors.forename: D
authors.initials: D
authors.lastname: Rusnak
authors.forename: L
authors.initials: L
authors.lastname: Shewchuk
authors.forename: J M
authors.initials: JM
authors.lastname: Veal
authors.forename: D H
authors.initials: DH
authors.lastname: Walker
authors.forename: L F
authors.initials: LF
authors.lastname: Kuyper
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007510:Isatin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016196:S Phase / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; D007211:Indoles; D013449:Sulfonamides; D007510:Isatin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases