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: Nassima Oumata, Karima Bettayeb, Yoan Ferandin, Luc Demange, Angela Lopez-Giral, Marie-Lorène Goddard, Vassilios Myrianthopoulos, Emmanuel Mikros, Marc Flajolet, Paul Greengard, Laurent Meijer, Hervé Galons
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 17 Pg. 5229-42 (Sep 11 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18698753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Protein Kinase Inhibitors
• Purines
• Roscovitine
• Casein Kinase I
• Cyclin-Dependent Kinases

Topics

• Amyloid beta-Peptides (antagonists & inhibitors, biosynthesis)
• Animals
• Binding Sites
• Casein Kinase I (antagonists & inhibitors)
• Cell Line
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Protein Kinase Inhibitors (analogs & derivatives, chemistry, pharmacology)
• Purines (chemistry, pharmacology)
• Roscovitine
• Structure-Activity Relationship