@article{3062308,
    title = "Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1",
    author = "Oumata, N. and Bettayeb, K. and Ferandin, Y. and Demange, L. and Lopez-Giral, A. and Goddard, M.-L. and Myrianthopoulos, V. and Mikros, E. and Flajolet, M. and Greengard, P. and Meijer, L. and Galons, H.",
    journal = "Journal of Medicinal Chemistry",
    year = "2008",
    volume = "51",
    number = "17",
    pages = "5229-5242",
    issn = "0022-2623, 1520-4804",
    doi = "10.1021/jm800109e",
    keywords = "2 (1 hydroxybut 2 ylamino) 6 [3 (2 pyridyl)phenylamino] 9 isopropylpurine;  amyloid beta protein;  casein kinase I;  casein kinase Ialpha;  cyclin B;  cyclin dependent kinase;  cyclin dependent kinase 1;  cyclin dependent kinase 5;  purine derivative;  roscovitine;  tau protein;  unclassified drug, Alzheimer disease;  amino acid sequence;  article;  chemical structure;  drug activity;  drug synthesis;  enzyme activity;  enzyme inhibition;  human;  human cell;  molecular model;  neurofibrillary tangle;  structure analysis, Amyloid beta-Protein;  Animals;  Binding Sites;  Casein Kinase I;  Cell Line;  Cyclin-Dependent Kinases;  Humans;  Inhibitory Concentration 50;  Models, Molecular;  Protein Kinase Inhibitors;  Purines;  Structure-Activity Relationship",
    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-β 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 (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1δ provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-β in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers. © 2008 American Chemical Society."
}