Discovery of Selective, Substrate-Competitive, and Passive Membrane Permeable Glycogen Synthase Kinase-3 beta Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling of New C-Glycosylflavones

作者：Liang Zhibin; Li Qing X^*

来源：ACS Chemical Neuroscience, 2018, 9(5): 1166-1183.

DOI：10.1021/acschemneuro.8b00010

• C-Glycosylflavone
• computer-aided drug design
• glycogen synthase kinase-3
• substrate-competitive inhibitor
• kinase selectivity
• tauopathy
• Alzheimer's disease

Glycogen synthase kinase-3 beta (GSK-beta) is a key enzyme responsible for tau hyperphosphorylation and is a viable therapeutic target of Alzheimer's disease (AD). We developed a new class of GSK-3 beta inhibitors based on the 6-C-glycosylflavone isoorientin (1). The new inhibitors are passive membrane permeable and constitutively attenuate GSK-3 beta mediated tau hyperphosphorylation and amyloid neurotoxicity in an AD cellular model. Enzymatic assays and kinetic studies demonstrated that compound 30 is a GSK-3 beta substrate-competitive inhibitor with distinct kinase selectivity, isoform-selectivity and over 310-fold increased potency as compared to 1. Structure-activity relationship analyses and in silico modeling suggest the mechanism of actions by which the hydrophobic, pi-cation, and orthogonal multipolar interactions of 30 with the substrate site are critical for the GSK-3 beta inhibition and selectivity. The results provide new insights into GSK-3 beta drug discovery. The new inhibitors are valuable chemical probes and drug leads with therapeutic potential to tackle AD and other GSK-3 beta relevant diseases.

• 出版日期2018-5