Roscovitine-Derived, Dual-Specificity Inhibitors of Cyclin-Dependent Kinases and Casein Kinases 1.
In: ISSN: 0022-2623, 2008
academicJournal
Zugriff:
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.
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Roscovitine-Derived, Dual-Specificity Inhibitors of Cyclin-Dependent Kinases and Casein Kinases 1.
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Autor/in / Beteiligte Person: | Oumata, Nassima ; Bettayeb, Karima ; Ferandin, Yoan ; Demange, Luc ; Lopez-Giral, Angela ; Goddard, Marie-Lore?ne ; Myrianthopoulos, Vassilios ; Mikros, Emmanuel ; Flajolet, Marc ; Greengard, Paul ; Meijer, Laurent ; Galons, Herve ; Molécules et cibles thérapeutiques (MCT) ; Station biologique de Roscoff Roscoff (SBR) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Laboratoire des Amino-acides Peptides et Protéines (LAPP) ; Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) ; Institut des Biomolécules Max Mousseron Pôle Chimie Balard (IBMM) ; Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) ; Institut de Chimie des Substances Naturelles (ICSN) ; Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Laboratory of Molecular and Cellular Neuroscience ; Rockefeller University New York ; Institut de biologie et chimie des protéines Lyon (IBCP) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS) |
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Zeitschrift: | ISSN: 0022-2623, 2008 |
Veröffentlichung: | HAL CCSD ; American Chemical Society, 2008 |
Medientyp: | academicJournal |
DOI: | 10.1021/jm800109e |
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