1. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases.
- Author
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Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, and Meijer L
- Subjects
- Animals, Antibiotics, Antineoplastic chemistry, Apoptosis drug effects, Cell Cycle drug effects, Cell Division drug effects, Cell Line, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases chemistry, HL-60 Cells, Humans, Indigo Carmine, Indoles chemistry, Indoles pharmacokinetics, Indoles pharmacology, Isatin chemistry, Isatin pharmacokinetics, Isatin pharmacology, Jurkat Cells, K562 Cells, Leukemia L1210, Medicine, Chinese Traditional, Mice, Models, Molecular, Molecular Conformation, Protein Conformation, Protein Serine-Threonine Kinases chemistry, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins chemistry, Spodoptera, Transfection, Antibiotics, Antineoplastic pharmacology, CDC2-CDC28 Kinases, Cyclin-Dependent Kinases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Here we identify indirubin and its analogues as potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell cycle. These results have implications for therapeutic optimization of indigoids.
- Published
- 1999
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