Na Zeng, Guichen Ye, Mengchu Zheng, Guangyuan Liu, Sihan Zhang, Siyang Ma, Zhiyu Xia, Yirong Zhou, Shaogang Wang, Qidong Xia
{"title":"Discovery and validation of indole nitroolefins as novel covalent GPX4 inhibitors for inducing ferroptosis in urological cancers.","authors":"Na Zeng, Guichen Ye, Mengchu Zheng, Guangyuan Liu, Sihan Zhang, Siyang Ma, Zhiyu Xia, Yirong Zhou, Shaogang Wang, Qidong Xia","doi":"10.21147/j.issn.1000-9604.2025.03.09","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Ferroptosis represents a form of cell death characterized by the accumulation of iron dependent lipid peroxidation. This process culminates in membrane damage and cell lysis. One pivotal surveillance mechanism is induced by glutathione peroxidase 4 (GPX4). Furthermore, inhibition of GPX4 has been reported to hold a promise effect in cancer therapeutics.</p><p><strong>Methods: </strong>Computer-aided docking and small molecule probe were used for designed compounds. Flow cytometry was used to evaluate the ferroptosis. Animal experiments were taken to evaluate the <i>in vivo</i> effect of two compounds.</p><p><strong>Results: </strong>Based on our prior research, a series of twenty compounds with covalent binding potential was designed and synthesized. Under systematic evaluation, our team identified two small molecules 14 and 16, which significantly stabilized GPX4 thermal denaturation. Further investigations revealed that treatment with compounds 14 and 16 led to an increase in lipid peroxidation, oxidative stress, and other markers (C11, Fe<sup>2+</sup> and ROS) levels also increased. In both <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i> experiment, compounds 14 and 16 are found suppression effect on urological cancer cells.</p><p><strong>Conclusions: </strong>Compounds 14 and 16 deserve further works as lead compounds of novel docking models for finally discovering effective anti-tumor drug. Future research is needed to dissect their mechanism and exploits this scaffold for GPX4 inhibitor development.</p>","PeriodicalId":9882,"journal":{"name":"Chinese Journal of Cancer Research","volume":"37 3","pages":"404-416"},"PeriodicalIF":7.0000,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240241/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chinese Journal of Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21147/j.issn.1000-9604.2025.03.09","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: Ferroptosis represents a form of cell death characterized by the accumulation of iron dependent lipid peroxidation. This process culminates in membrane damage and cell lysis. One pivotal surveillance mechanism is induced by glutathione peroxidase 4 (GPX4). Furthermore, inhibition of GPX4 has been reported to hold a promise effect in cancer therapeutics.
Methods: Computer-aided docking and small molecule probe were used for designed compounds. Flow cytometry was used to evaluate the ferroptosis. Animal experiments were taken to evaluate the in vivo effect of two compounds.
Results: Based on our prior research, a series of twenty compounds with covalent binding potential was designed and synthesized. Under systematic evaluation, our team identified two small molecules 14 and 16, which significantly stabilized GPX4 thermal denaturation. Further investigations revealed that treatment with compounds 14 and 16 led to an increase in lipid peroxidation, oxidative stress, and other markers (C11, Fe2+ and ROS) levels also increased. In both invivo and invitro experiment, compounds 14 and 16 are found suppression effect on urological cancer cells.
Conclusions: Compounds 14 and 16 deserve further works as lead compounds of novel docking models for finally discovering effective anti-tumor drug. Future research is needed to dissect their mechanism and exploits this scaffold for GPX4 inhibitor development.
期刊介绍:
Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013.
CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.