Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?
The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment of chronic diseases such as leukemias. The antitumoral properties of indirubin appear to correlate with their antimitotic effects. Indirubins were recently described as potent (IC(50): 50-100 nm) inhibitors of cyclin-dependent kinases (CDKs). We report here that indirubins are also powerful inhibitors (IC(50): 5-50 nm) of an evolutionarily related kinase, glycogen synthase kinase-3beta (GSK-3 beta). Testing of a series of indoles and bis-indoles against GSK-3 beta, CDK1/cyclin B, and CDK5/p25 shows that only indirubins inhibit these kinases. The structure-activity relationship study also suggests that indirubins bind to GSK-3 beta's ATP binding pocket in a way similar to their binding to CDKs, the details of which were recently revealed by crystallographic analysis. GSK-3 beta, along with CDK5, is responsible for most of the abnormal hyperphosphorylation of the microtubule-binding protein tau observed in Alzheimer's disease. Indirubin-3'-monoxime inhibits tau phosphorylation in vitro and in vivo at Alzheimer's disease-specific sites. Indirubins may thus have important implications in the study and treatment of neurodegenerative disorders. Indirubin-3'-monoxime also inhibits the in vivo phosphorylation of DARPP-32 by CDK5 on Thr-75, thereby mimicking one of the effects of dopamine in the striatum. Finally, we show that many, but not all, reported CDK inhibitors are powerful inhibitors of GSK-3 beta. To which extent these GSK-3 beta effects of CDK inhibitors actually contribute to their antimitotic and antitumoral properties remains to be determined. Indirubins constitute the first family of low nanomolar inhibitors of GSK-3 beta to be described.
Leclerc
S
S
CNRS, Cell Cycle Group, Station Biologique, BP 74, Roscoff 29682 Cedex, Bretagne, France.
Garnier
M
M
Hoessel
R
R
Marko
D
D
Bibb
J A
JA
Snyder
G L
GL
Greengard
P
P
Biernat
J
J
Wu
Y Z
YZ
Mandelkow
E M
EM
Eisenbrand
G
G
Meijer
L
L
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000032:analysis / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology / Q000031:analogs & derivatives; D016875:tau Proteins / Q000378:metabolism*
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D019926:Cyclin B; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D010880:Piperidines; D016875:tau Proteins; D010769:Phosphothreonine; C077990:alvocidib; C054852:7-hydroxystaurosporine; D000255:Adenosine Triphosphate; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D019311:Staurosporine; C027185:indirubin