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

• Published in: Journal of medicinal chemistry 2001-12, Vol.44 (25), p.4339-4358
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; CDC2-CDC28 Kinases; Crystallography, X-Ray; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; G1 Phase - drug effects; General aspects; Humans; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Isatin - analogs & derivatives; Isatin - chemical synthesis; Isatin - chemistry; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Protein-Serine-Threonine Kinases - antagonists & inhibitors; S Phase - drug effects; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemistry; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010117d

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.