Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases.
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.
Hoessel
R
R
Department of Chemistry, University of Kaiserslautern, Germany.
Leclerc
S
S
Endicott
J A
JA
Nobel
M E
ME
Lawrie
A
A
Tunnah
P
P
Leost
M
M
Damiens
E
E
Marie
D
D
Marko
D
D
Niederberger
E
E
Tang
W
W
Eisenbrand
G
G
Meijer
L
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007203:Indigo Carmine; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007510:Isatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019169:Jurkat Cells; D020014:K562 Cells; D007939:Leukemia L1210; D008516:Medicine, Chinese Traditional; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D018411:Spodoptera; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007211:Indoles; D011994:Recombinant Proteins; D007510:Isatin; D007203:Indigo Carmine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C027185:indirubin