Highly potent and specific GSK-3β inhibitors that block tau phosphorylation and decrease α-synuclein protein expression in a cellular model of Parkinson's disease

Research by Klein and co-workers suggests that the inhibition of GSK-3β by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3β, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3β inhibition, only ligands with a K. value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3β-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of α-Syn protein expression. We conclude that the GSK-3β inhibitors described herein offer promise in defending cells against MPP⁺-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.