一种新型吡咯[2,3-b]吡啶化合物作为治疗阿尔茨海默病的糖原合成酶激酶3β抑制剂的鉴定。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Qing-Qing Xun, Jing Zhang, Lei Feng, Yu-Ying Ma, Ying Li, Xiao-Long Shi
{"title":"一种新型吡咯[2,3-b]吡啶化合物作为治疗阿尔茨海默病的糖原合成酶激酶3β抑制剂的鉴定。","authors":"Qing-Qing Xun, Jing Zhang, Lei Feng, Yu-Ying Ma, Ying Li, Xiao-Long Shi","doi":"10.1080/14756366.2025.2466846","DOIUrl":null,"url":null,"abstract":"<p><p>Herein, a novel pyrrolo[2,3-<i>b</i>]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, <b>S01</b>, was rationally designed and synthesised to target Alzheimer's disease (AD). <b>S01</b> inhibited GSK-3β, with an IC<sub>50</sub> of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that <b>S01</b> efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, <b>S01</b> 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, <b>S01</b> substantially ameliorated dyskinesia in AlCl<sub>3</sub>-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 <b>S01</b> in vivo. Our findings suggested that <b>S01</b> is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2466846"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843656/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of a novel pyrrolo[2,3-<i>b</i>]pyridine compound as a potent glycogen synthase kinase 3β inhibitor for treating Alzheimer's disease.\",\"authors\":\"Qing-Qing Xun, Jing Zhang, Lei Feng, Yu-Ying Ma, Ying Li, Xiao-Long Shi\",\"doi\":\"10.1080/14756366.2025.2466846\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Herein, a novel pyrrolo[2,3-<i>b</i>]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, <b>S01</b>, was rationally designed and synthesised to target Alzheimer's disease (AD). <b>S01</b> inhibited GSK-3β, with an IC<sub>50</sub> of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that <b>S01</b> efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, <b>S01</b> 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, <b>S01</b> substantially ameliorated dyskinesia in AlCl<sub>3</sub>-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 <b>S01</b> in vivo. Our findings suggested that <b>S01</b> is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"40 1\",\"pages\":\"2466846\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843656/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2025.2466846\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2025.2466846","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

本文合理设计合成了一种新型吡咯[2,3-b]吡啶基糖原合成酶激酶3β (GSK-3β)抑制剂S01,用于治疗阿尔茨海默病(AD)。S01抑制GSK-3β的IC50为0.35±0.06 nM,对24种结构相似的激酶具有可接受的选择性。Western blotting检测结果显示,S01有效地增加了p-GSK-3β-Ser9的表达,并呈剂量依赖性地降低了p-tau-Ser396的表达。在体外细胞实验中,S01对SH-SY5Y细胞表现出较低的细胞毒性,显著上调β-catenin及神经发生相关生物标志物的表达,有效促进分化的神经突的生长。此外,在相同条件下,浓度为0.12 μM的S01显著改善alcl3诱导的斑马鱼AD模型的运动障碍,其效果优于多奈哌齐(8 μM)。急性毒性实验进一步证实了S01在体内的安全性。我们的研究结果表明,S01是一种潜在的GSK-3β抑制剂,可以作为治疗AD的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of a novel pyrrolo[2,3-b]pyridine compound as a potent glycogen synthase kinase 3β inhibitor for treating Alzheimer's disease.

Herein, a novel pyrrolo[2,3-b]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, S01, was rationally designed and synthesised to target Alzheimer's disease (AD). S01 inhibited GSK-3β, with an IC50 of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that S01 efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, S01 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, S01 substantially ameliorated dyskinesia in AlCl3-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 S01 in vivo. Our findings suggested that S01 is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信