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 inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3beta, 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.
Polychronopoulos
Panagiotis
P
Laboratory of Pharmacognosy and Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Magiatis
Prokopios
P
Skaltsounis
Alexios-Leandros
AL
Myrianthopoulos
Vassilios
V
Mikros
Emmanuel
E
Tarricone
Aldo
A
Musacchio
Andrea
A
Roe
S Mark
SM
Pearl
Laurence
L
Leost
Maryse
M
Greengard
Paul
P
Meijer
Laurent
L
D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C027185:indirubin