{"title":"通过基于结构的药效学建模、虚拟筛选、分子对接、分子动力学模拟研究和生物学评价,发现治疗结直肠癌的新型强效 AXL/HDAC2 双靶向抑制剂。","authors":"Xiao Qiao, Xiangyu Wu, Shutong Chen, Miao-Miao Niu, Huilian Hua, Yan Zhang","doi":"10.1080/14756366.2023.2295241","DOIUrl":null,"url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant <i>in vivo</i> antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2295241"},"PeriodicalIF":5.6000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763849/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation.\",\"authors\":\"Xiao Qiao, Xiangyu Wu, Shutong Chen, Miao-Miao Niu, Huilian Hua, Yan Zhang\",\"doi\":\"10.1080/14756366.2023.2295241\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant <i>in vivo</i> antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"39 1\",\"pages\":\"2295241\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763849/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2023.2295241\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/12/22 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/10.1080/14756366.2023.2295241","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
结直肠癌(CRC)是全球最常见的癌症之一。目前,由于肿瘤发生机制复杂,同时抑制多个靶点是一种重要的抗癌策略。最近的研究表明,受体酪氨酸激酶AXL(AXL)和组蛋白去乙酰化酶2(HDAC2)与结直肠癌密切相关。在此,我们通过虚拟筛选确定了五种同时靶向 AXL 和 HDAC2 的热门化合物。抑制实验显示,这些命中化合物在纳摩尔范围内对AXL和HDAC2具有强效抑制作用。其中,Hit-3的抑制效果最强,优于阳性对照组。此外,MD 试验表明,Hit-3 能与 AXL 和 HDAC2 的活性口袋稳定结合。进一步的 MTT 试验表明,Hit-3 具有很强的抗增殖活性。最重要的是,Hit-3 在异种移植模型中表现出显著的体内抗肿瘤疗效。总之,这项研究首次发现了用于结直肠癌治疗的 AXL/HDAC2 双靶向抑制剂。
Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation.
Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.
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.