Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent...

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Published in:Journal of medicinal chemistry 2004-02, Vol.47 (4), p.935-946
Main Authors: Polychronopoulos, Panagiotis, Magiatis, Prokopios, Skaltsounis, Alexios-Leandros, Myrianthopoulos, Vassilios, Mikros, Emmanuel, Tarricone, Aldo, Musacchio, Andrea, Roe, S. Mark, Pearl, Laurence, Leost, Maryse, Greengard, Paul, Meijer, Laurent
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - chemistry
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Glycogen Synthase Kinase 3 - chemistry
Indoles - chemical synthesis
Indoles - chemistry
Medical sciences
Miscellaneous
Models, Molecular
Oximes - chemical synthesis
Oximes - chemistry
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3β, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm031016d