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

ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) 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? inhibitors based on the 6- C-glycosylflavone isoorientin (1). The new inhibitors are passive membrane permeable and constitutively attenuate GSK-3? mediated tau hyperphosphorylation and amyloid neurotoxicity in an AD cellular model. Enzymatic assays and kinetic studies demonstrated that compound 30 is a GSK-3? 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, ?-cation, and orthogonal multipolar interactions of 30 with the substrate site are critical for the GSK-3? inhibition and selectivity. The results provide new insights into GSK-3? drug discovery. The new inhibitors are valuable chemical probes and drug leads with therapeutic potential to tackle AD and other GSK-3? relevant diseases.

SUBMITTER: Liang Z 

PROVIDER: S-EPMC7368552 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature