Discovery and validation of indole nitroolefins as novel covalent GPX4 inhibitors for inducing ferroptosis in urological cancers.

IF 7 2区 医学 Q1 ONCOLOGY
Na Zeng, Guichen Ye, Mengchu Zheng, Guangyuan Liu, Sihan Zhang, Siyang Ma, Zhiyu Xia, Yirong Zhou, Shaogang Wang, Qidong Xia
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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 in vivo and in vitro 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.

吲哚硝基烯烷作为新型共价GPX4抑制剂在泌尿系统癌症中诱导铁凋亡的发现和验证。
目的:铁下垂是一种以铁依赖性脂质过氧化积累为特征的细胞死亡形式。这一过程最终导致膜损伤和细胞裂解。一个关键的监测机制是由谷胱甘肽过氧化物酶4 (GPX4)诱导的。此外,据报道,抑制GPX4在癌症治疗中具有良好的效果。方法:采用计算机辅助对接和小分子探针对设计的化合物进行检测。流式细胞术评价铁下垂。采用动物实验评价两种化合物的体内作用。结果:在前期研究的基础上,设计并合成了一系列具有共价结合电位的20个化合物。在系统评价下,我们团队确定了两个小分子14和16,它们显著地稳定了GPX4的热变性。进一步的研究表明,化合物14和16导致脂质过氧化、氧化应激和其他标志物(C11、Fe2+和ROS)水平升高。体内和体外实验均发现化合物14和16对泌尿系统癌细胞有抑制作用。结论:化合物14和16值得进一步作为新型对接模型的先导化合物,最终发现有效的抗肿瘤药物。未来的研究需要剖析它们的机制,并利用这种支架来开发GPX4抑制剂。
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来源期刊
自引率
9.80%
发文量
1726
审稿时长
4.5 months
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.
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