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

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-dihydr...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm010117d