Next-Generation Bcl-2 Inhibitors: Design and Evaluation of Indolyl-Triazole Derivatives with Anticancer Potential.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-18 DOI:10.1002/cmdc.202500265
Ahmed M Almehdi, Samar Damiati, Ihsan A Shehadi, Mohamed El-Sadek, Arwyn T Jones, Abdalla El-Kabalawy, Yasmina Lashine, Yogendra Nayak, Sameh S M Soliman, Andrew D Westwell, Rania Hamdy
{"title":"Next-Generation Bcl-2 Inhibitors: Design and Evaluation of Indolyl-Triazole Derivatives with Anticancer Potential.","authors":"Ahmed M Almehdi, Samar Damiati, Ihsan A Shehadi, Mohamed El-Sadek, Arwyn T Jones, Abdalla El-Kabalawy, Yasmina Lashine, Yogendra Nayak, Sameh S M Soliman, Andrew D Westwell, Rania Hamdy","doi":"10.1002/cmdc.202500265","DOIUrl":null,"url":null,"abstract":"<p><p>The Bcl-2 protein family plays a critical role in regulating apoptosis, making it a key target for cancer therapy. In this study, a series of novel Bcl-2 inhibitors have been designed, synthesized, and evaluated. To disrupt the interactions between anti-apoptotic Bcl-2 and pro-apoptotic proteins, compounds were developed based on essential pharmacophoric features. Among the tested compounds, R4, R14, R17, and R23 demonstrated potent anticancer activity with sub-micromolar IC<sub>50</sub> concentrations across various Bcl-2 expressing human cancer cell lines (IC<sub>50</sub> ranges: 1.46-7.67 µM for cancer cells). ELISA binding assays further validated the efficacy of R4, R14, and R23, showcasing their potency with IC<sub>50</sub> values ranging from 0.25 to 0.63 µM, compared to gossypol and ABT-199 (venetoclax), with IC<sub>50</sub> values of 0.6 and 0.038 µM, respectively. Furthermore, the R23 revealed a significant induction of late and early apoptosis and cell cycle arrest at G1 phase. Noteworthy, R23 emerged as a promising candidate with unique computational analysis, showing superior displacement of hydration sites and higher ΔG values in WaterMap studies. Moreover, molecular dynamics simulations reveal low root mean square deviation fluctuations, indicating strong and stable interactions with Bcl-2. These findings underscore the therapeutic potential of R23 as a Bcl-2 inhibitor.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500265"},"PeriodicalIF":3.4000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500265","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

The Bcl-2 protein family plays a critical role in regulating apoptosis, making it a key target for cancer therapy. In this study, a series of novel Bcl-2 inhibitors have been designed, synthesized, and evaluated. To disrupt the interactions between anti-apoptotic Bcl-2 and pro-apoptotic proteins, compounds were developed based on essential pharmacophoric features. Among the tested compounds, R4, R14, R17, and R23 demonstrated potent anticancer activity with sub-micromolar IC50 concentrations across various Bcl-2 expressing human cancer cell lines (IC50 ranges: 1.46-7.67 µM for cancer cells). ELISA binding assays further validated the efficacy of R4, R14, and R23, showcasing their potency with IC50 values ranging from 0.25 to 0.63 µM, compared to gossypol and ABT-199 (venetoclax), with IC50 values of 0.6 and 0.038 µM, respectively. Furthermore, the R23 revealed a significant induction of late and early apoptosis and cell cycle arrest at G1 phase. Noteworthy, R23 emerged as a promising candidate with unique computational analysis, showing superior displacement of hydration sites and higher ΔG values in WaterMap studies. Moreover, molecular dynamics simulations reveal low root mean square deviation fluctuations, indicating strong and stable interactions with Bcl-2. These findings underscore the therapeutic potential of R23 as a Bcl-2 inhibitor.

下一代Bcl-2抑制剂:具有抗癌潜力的吲哚-三唑衍生物的设计和评价。
Bcl-2蛋白家族在调节细胞凋亡中起关键作用,使其成为癌症治疗的关键靶点。本研究设计、合成并评价了一系列新型Bcl-2抑制剂。为了破坏抗凋亡Bcl-2和促凋亡蛋白之间的相互作用,根据基本的药效特征开发了化合物。在所测试的化合物中,R4、R14、R17和R23在各种表达Bcl-2的人类癌细胞系中表现出亚微摩尔的IC50浓度(IC50范围:1.46-7.67µM),具有较强的抗癌活性。ELISA结合实验进一步验证了R4、R14和R23的有效性,显示它们的IC50值在0.25 ~ 0.63µM之间,而棉酚和ABT-199 (venetoclax)的IC50值分别为0.6和0.038µM。此外,R23在G1期显著诱导晚期和早期凋亡和细胞周期阻滞。值得注意的是,R23通过独特的计算分析成为有希望的候选者,在WaterMap研究中显示出优越的水化位点位移和更高的ΔG值。此外,分子动力学模拟显示低均方根偏差波动,表明与Bcl-2强而稳定的相互作用。这些发现强调了R23作为Bcl-2抑制剂的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
×
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