Design, synthesis and evaluation of diphenyl ether-based kaiso inhibitors with enhanced potency

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-04 DOI:10.1016/j.bmcl.2025.130158

Taofeng Lin , Zhongqi Li , Juanchan Yuan , Tinfeng Ren , Wan Pang , Songhui Xu

{"title":"Design, synthesis and evaluation of diphenyl ether-based kaiso inhibitors with enhanced potency","authors":"Taofeng Lin , Zhongqi Li , Juanchan Yuan , Tinfeng Ren , Wan Pang , Songhui Xu","doi":"10.1016/j.bmcl.2025.130158","DOIUrl":null,"url":null,"abstract":"<div><div>Kaiso, a potential target for the treatment of lung cancer. Our research focuses on Kaiso inhibitros. Through virtual screening and molecular dynamic simulations, we discovered a promising Kaiso inhibitor called compound <strong>5</strong> (ZINC20577650). By modifying the structure of compound <strong>5</strong>, a series of novel Kaiso inhibitors that contain a diphenyl ether ring were synthesized. Among them, compound <strong>20</strong> exhibited the strongest inhibitory activity against A549 cells (IC<sub>50</sub> = 0.34 μM). Notably, its inhibitory activity surpassed that of the positive control <strong>MIRA-1</strong> (IC<sub>50</sub> = 654.065 μM). Molecular docking and dynamic studies revealed that the binding of the compound's amino and ester moieties to the active site of kaiso protein, as well as the extension of the benzene ring towards the Asn561 position in the cavity, contributed significantly to its potency. These findings provide valuable insights for the development of new Kaiso inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130158"},"PeriodicalIF":2.5000,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X25000678","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Kaiso, a potential target for the treatment of lung cancer. Our research focuses on Kaiso inhibitros. Through virtual screening and molecular dynamic simulations, we discovered a promising Kaiso inhibitor called compound 5 (ZINC20577650). By modifying the structure of compound 5, a series of novel Kaiso inhibitors that contain a diphenyl ether ring were synthesized. Among them, compound 20 exhibited the strongest inhibitory activity against A549 cells (IC₅₀ = 0.34 μM). Notably, its inhibitory activity surpassed that of the positive control MIRA-1 (IC₅₀ = 654.065 μM). Molecular docking and dynamic studies revealed that the binding of the compound's amino and ester moieties to the active site of kaiso protein, as well as the extension of the benzene ring towards the Asn561 position in the cavity, contributed significantly to its potency. These findings provide valuable insights for the development of new Kaiso inhibitors.

Abstract Image

查看原文本刊更多论文

设计、合成和评估效力更强的二苯醚基凯索抑制剂。

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

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.