Paullones are potent inhibitors of glycogen synthase kinase-3 beta and cyclin-dependent kinase 5/p25

Paullones constitute a new family of benzazepinones with promising antitumo ral properties. They were recently described as potent, ATP-competitive, in hibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We h ere report that paullones also act as very potent inhibitors of glycogen sy nthase kinase-3 beta (GSK-3 beta) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyper phosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerat ive 'taupathies'. Alsterpaullone, the most active paullone, was demonstrate d to act by competing with ATP for binding to GSK-3 beta. Alsterpaullone in hibits the phosphorylation of tau in vivo at sites which are typically phos phorylated by GSK-3 beta in Alzheimer's disease. Alsterpaullone also inhibi ts the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum sli ces in vitro. This dual specificity of paullones may turn these compounds i nto very useful tools for the study and possibly treatment of neurodegenera tive and proliferative disorders.