Xun Qing-Qing, Zhang Jing, Feng Lei, Ma Yu-Ying, Li Ying, Shi Xiao-Long
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China.
School of Clinical Medicine, Jining Medical University, Jining, Shandong, China.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2466846. doi: 10.1080/14756366.2025.2466846. Epub 2025 Feb 20.
Herein, a novel pyrrolo[2,3-]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, , was rationally designed and synthesised to target Alzheimer's disease (AD). inhibited GSK-3β, with an IC of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, substantially ameliorated dyskinesia in AlCl-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of in vivo. Our findings suggested that is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.
在此，一种新型的基于吡咯并[2,3 - ]吡啶的糖原合酶激酶3β（GSK - 3β）抑制剂被合理设计并合成，用于靶向治疗阿尔茨海默病（AD）。该抑制剂对GSK - 3β具有抑制作用，其IC50为0.35±0.06 nM，对24种结构相似的激酶具有可接受的激酶选择性。蛋白质免疫印迹分析表明，该抑制剂能以剂量依赖的方式有效增加p - GSK - 3β - Ser9的表达，并降低p - tau - Ser396的水平。体外细胞实验表明，该抑制剂对SH - SY5Y细胞具有低细胞毒性，显著上调β - 连环蛋白和神经发生相关生物标志物的表达，并有效促进分化神经元神经突的生长。此外，在浓度为0.12 μM时，该抑制剂能显著改善氯化铝诱导的斑马鱼AD模型中的运动障碍，在相同条件下比多奈哌齐（8 μM）更有效。急性毒性实验进一步证实了该抑制剂在体内的安全性。我们的研究结果表明，该抑制剂是一种有前景的GSK - 3β抑制剂，可作为治疗AD的候选药物进行测试。
