title: Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases.
abstract: 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.
authors.affiliation: Laboratory of Pharmacognosy and Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Polychronopoulos
authors.forename: Prokopios
authors.initials: P
authors.lastname: Magiatis
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.forename: Vassilios
authors.initials: V
authors.lastname: Myrianthopoulos
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.forename: Aldo
authors.initials: A
authors.lastname: Tarricone
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Laurence
authors.initials: L
authors.lastname: Pearl
authors.forename: Maryse
authors.initials: M
authors.lastname: Leost
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: 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
chemical_list: D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C027185:indirubin