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

中文翻译：

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选择性，底物竞争性和被动膜可渗透的糖原合酶激酶3β抑制剂的发现：合成，生物学评估和新的C-糖基黄酮的分子建模。

糖原合酶激酶3β（GSK-3β）是负责tau过度磷酸化的关键酶，是阿尔茨海默氏病（AD）的可行治疗靶标。我们基于6- C-糖基黄酮异东ient素（1）开发了一类新的GSK-3β抑制剂。新的抑制剂具有被动膜渗透性，并能在AD细胞模型中减弱GSK-3β介导的tau过度磷酸化和淀粉样蛋白神经毒性。酶法测定和动力学研究表明，化合物30是GSK-3β底物竞争性抑制剂，与1相比，具有明显的激酶选择性，同工型选择性和超过310倍的增强效力。结构-活性之间的关系分析和计算机模拟表明，作用机理决定了30与底物部位的疏水，π-阳离子和正交多极相互作用对GSK-3β的抑制和选择性至关重要。结果为GSK-3β药物发现提供了新的见解。新型抑制剂是有价值的化学探针和药物引线，具有治疗AD和其他GSK-3β相关疾病的治疗潜力。