Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3ß inhibitors to activate Wnt/ß-catenin pathway.

Deregulation of Wnt/ß-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and glycogen synthase kinase 3ß (GSK-3ß), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3ß inhibitors by rational-design and synthesis, which show high selectivity against GSK-3ß over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/ß-catenin pathway. The structure-activity relationship of these GSK-3ß inhibitors was also explored by in silico molecular docking.