Τίτλος:
Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Oumata, N.
Bettayeb, K.
Ferandin, Y.
Demange, L.
Lopez-Giral, A.
Goddard, M.-L.
Myrianthopoulos, V.
Mikros, E.
Flajolet, M.
Greengard, P.
Meijer, L.
Galons, H.
Περιοδικό:
Journal of Medicinal Chemistry
Λέξεις-κλειδιά:
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
