Details

Autor(en) / Beteiligte

• Bramson, H. Neal
• Corona, John
• Davis, Stephen T
• Dickerson, Scott H
• Edelstein, Mark
• Frye, Stephen V
• Gampe, Robert T
• Harris, Phil A
• Hassell, Anne
• Holmes, William D
• Hunter, Robert N
• Lackey, Karen E
• Lovejoy, Brett
• Luzzio, Michael J
• Montana, Val
• Rocque, Warren J
• Rusnak, David
• Shewchuk, Lisa
• Veal, James M
• Walker, Duncan H
• Kuyper, Lee F

Titel

Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2):  Design, Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis

Ist Teil von

• Journal of medicinal chemistry, 2001-12, Vol.44 (25), p.4339-4358

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2001

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 ∼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.