title: Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1.
abstract: Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-beta peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC 50: 220 nM), CDK5/p25 (IC 50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1delta provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-beta in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.
authors.affiliation: Laboratoire de Chimie Organique 2, INSERM U 648, Universite Paris-Descartes, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France.
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
authors.forename: Angela
authors.initials: A
authors.lastname: Lopez-Giral
authors.forename: Marie-Lorène
authors.initials: ML
authors.lastname: Goddard
authors.forename: Vassilios
authors.initials: V
authors.lastname: Myrianthopoulos
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D001665:Binding Sites; D047389:Casein Kinase I / Q000037:antagonists & inhibitors*; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D000077546:Roscovitine; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D047389:Casein Kinase I; D018844:Cyclin-Dependent Kinases