[摘要]：Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key mol. features of Alzheimer's disease, prodn. of amyloid-b 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 compds. were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivs. displayed potent inhibition of both CDKs and CK1. In particular, deriv. I was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC50: 14 nM). Modeling of these mols. into the ATP-binding pocket of CK1d provided a rationale for the increased selectivity toward this kinase. I was able to prevent the CK1-dependent prodn. of amyloid-b in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.
