Discovery and structural-activity relationship of N-benzyl-2-fluorobenzamides as EGFR/HDAC3 dual-target inhibitors for the treatment of triple-negative breast cancer.
{"title":"Discovery and structural-activity relationship of N-benzyl-2-fluorobenzamides as EGFR/HDAC3 dual-target inhibitors for the treatment of triple-negative breast cancer.","authors":"Gong-Hui Ge, Shuai Guo, Ting-Ting Li, Yan-Ping Wang, Li-Rong Liu, Wen-Hui Yu, Hao Hu, Yi-Meng Zheng, Jing-Han Yan, Ying-Hao Sun, Jing-Wei Liang, Fan-Hao Meng, Ting-Jian Zhang","doi":"10.1016/j.bmcl.2025.130362","DOIUrl":null,"url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) and histone deacetylase 3 (HDAC3) synergistically drive malignant progression in triple-negative breast cancer (TNBC). In this study, a series of N-benzyl-2-fluorobenzamide derivatives (11-43) were identified as EGFR/HDAC3 dual-target inhibitors. Among them, compound 38 exhibited the most promising activity, with IC₅₀ values of 20.34 nM and 1.09 μM against EGFR and HDAC3, respectively. Molecular modeling revealed that the 2-fluorobenzamide moiety of 38 chelates with Zn<sup>2+</sup> in the active channel of HDAC3, while the 4-fluorobenzyl group occupies the ATP-binding pocket of EGFR, exercising a dual-target binding function. In vitro experiments demonstrated that 38 exhibited superior anti-proliferative activity (IC₅₀ = 1.98 μM) against MDA-MB-231 cells compared to chidamide (IC₅₀ = 24.37 μM), inducing 74.15 % inhibition of cell migration and 57.4 % late-stage apoptosis. In vivo studies revealed that 38 (30 mg/kg/day) suppressed tumor growth by 34.78 % without significant toxicity. Collectively, 38 represents a novel dual EGFR/HDAC3 inhibitor that shows promising potential for providing new therapeutic insights into TNBC treatment.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130362"},"PeriodicalIF":2.2000,"publicationDate":"2025-12-01","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://doi.org/10.1016/j.bmcl.2025.130362","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/5 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Epidermal growth factor receptor (EGFR) and histone deacetylase 3 (HDAC3) synergistically drive malignant progression in triple-negative breast cancer (TNBC). In this study, a series of N-benzyl-2-fluorobenzamide derivatives (11-43) were identified as EGFR/HDAC3 dual-target inhibitors. Among them, compound 38 exhibited the most promising activity, with IC₅₀ values of 20.34 nM and 1.09 μM against EGFR and HDAC3, respectively. Molecular modeling revealed that the 2-fluorobenzamide moiety of 38 chelates with Zn2+ in the active channel of HDAC3, while the 4-fluorobenzyl group occupies the ATP-binding pocket of EGFR, exercising a dual-target binding function. In vitro experiments demonstrated that 38 exhibited superior anti-proliferative activity (IC₅₀ = 1.98 μM) against MDA-MB-231 cells compared to chidamide (IC₅₀ = 24.37 μM), inducing 74.15 % inhibition of cell migration and 57.4 % late-stage apoptosis. In vivo studies revealed that 38 (30 mg/kg/day) suppressed tumor growth by 34.78 % without significant toxicity. Collectively, 38 represents a novel dual EGFR/HDAC3 inhibitor that shows promising potential for providing new therapeutic insights into TNBC treatment.
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.