MULTI-SUBSTRATE TYPE INHIBITORS FOR CDC2 KINASE AND THEIR EVALUATION AS SELECTIVE CELL-CYCLE INHIBITORS

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Protein kinases play a significan role in the signal transduction in cell, and are essential enzymes in maintaining norma cell functions. Protein kinases constitue a diverse family of related enzymes, which have similar structures in their catalytic sites. Therefore, it has been a difficult and challenging task to develop their selective inhibitors. We designed new inhibitors which have multisubstrate type structures (IV-VIII), i.e.bisindolylmaleimide for the ATP-binding site of the enzyme, tetrapeptide for the peptide-binding sites, and a spacer linking these units. In the in vitro inhibition assay using activated complex of cdc2 kinase-cycline B,new compounds (Va and VIb) were found to have potent inhibitory activities (Table).