• H N Bramson, J Corona, S T Davis, S H Dickerson, M Edelstein, S V Frye, R T Gampe, P A Harris, A Hassell, W D Holmes, R N Hunter, K E Lackey, B Lovejoy, M J Luzzio, V Montana, W J Rocque, D Rusnak, L Shewchuk, J M Veal, D H Walker, and L F Kuyper.
• GlaxoSmithKline Inc., Five Moore Drive, Research Triangle Park, North Carolina 27709, USA.
• J. Med. Chem. 2001 Dec 6; 44 (25): 4339-58.

AbstractTwo 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.

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