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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibiotics, Antineoplastic / chemistry
-
Antibiotics, Antineoplastic / pharmacology*
-
Apoptosis / drug effects
-
CDC2-CDC28 Kinases*
-
Cell Cycle / drug effects
-
Cell Division / drug effects
-
Cell Line
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinases / antagonists & inhibitors*
-
Cyclin-Dependent Kinases / chemistry
-
Enzyme Inhibitors / pharmacology*
-
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 / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / chemistry
-
Recombinant Proteins / antagonists & inhibitors
-
Recombinant Proteins / chemistry
-
Spodoptera
-
Transfection
Substances
-
Antibiotics, Antineoplastic
-
Enzyme Inhibitors
-
Indoles
-
Recombinant Proteins
-
Isatin
-
Indigo Carmine
-
Protein Serine-Threonine Kinases
-
CDC2-CDC28 Kinases
-
CDK2 protein, human
-
Cdk2 protein, mouse
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinases
-
indirubin