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Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2): Design, Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis
Open accessAbstract
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.
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Fry, D. W., Harvey, P. J., Keller, P. R., Elliott, W. L., Meade, M., Trachet, E., Albassam, M., Zheng, X., Leopold, W. R., Pryer, N. K., et al. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.1427.3.11 · Cited by 1,236
Kozakov, D., Grove, L. E., Hall, D. R., Bohnuud, T., Mottarella, S. E., Luo, L., Xia, B., Beglov, D., & Vajda, S. (2015) · Nature Protocols · doi:10.1038/nprot.2015.043 · Cited by 648
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Metadata
- Authors
- Bramson, H. N., Corona, J., Davis, S. T., Dickerson, S. H., Edelstein, M., Frye, S. V., Gampe, R. T., Harris, P. A., Hassell, A., Holmes, W. D., Hunter, R. N., Lackey, K. E., Lovejoy, B., Luzzio, M. J., Montana, V., Rocque, W. J., Rusnak, D., Shewchuk, L., Veal, J. M., Walker, D. H., & Kuyper, L. F.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2001-11-02
- Volume
- 44
- Issue
- 25
- Pages
- 4339-4358
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2117263757
- Cited by
- 269
- References
- 0
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- green
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