title: Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors to activate Wnt/β-catenin pathway.
abstract: Deregulation of Wnt/β-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and glycogen synthase kinase 3β (GSK-3β), 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-3β inhibitors by rational-design and synthesis, which show high selectivity against GSK-3β over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/β-catenin pathway. The structure-activity relationship of these GSK-3β inhibitors was also explored by in silico molecular docking.
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yue
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Lu
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: quanjm@pkusz.edu.cn.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Quan
mesh_terms: D001665:Binding Sites; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D054833:Isoindoles; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3
keywords: CDK2; GSK-3β; Inhibitor; Neurodegenerative diseases; Wnt/β-catenin pathway