2. Academic Validation
  3. Discovery and structural-activity relationship of N-benzyl-2-fluorobenzamides as EGFR/HDAC3 dual-target inhibitors for the treatment of triple-negative breast cancer

Discovery and structural-activity relationship of N-benzyl-2-fluorobenzamides as EGFR/HDAC3 dual-target inhibitors for the treatment of triple-negative breast cancer

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130362. doi: 10.1016/j.bmcl.2025.130362.
Gong-Hui Ge 1,  Shuai Guo 1,  Ting-Ting Li 1,  Yan-Ping Wang 1,  Li-Rong Liu 1,  Wen-Hui Yu 1,  Hao Hu 1,  Yi-Meng Zheng 1,  Jing-Han Yan 1,  Ying-Hao Sun 1,  Jing-Wei Liang 2,  Fan-Hao Meng 3,  Ting-Jian Zhang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Research, and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China.
  • 2 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, Hainan, China; School of Pharmacy, Hainan Medical University, Haikou 571199, Hainan, China.
  • 3 School of Pharmacy, Key Laboratory of Research, and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China. Electronic address: fhmeng@cmu.edu.cn.
  • 4 School of Pharmacy, Key Laboratory of Research, and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, Hainan, China. Electronic address: tjzhang@cmu.edu.cn.
PMID: 40763846 DOI: 10.1016/j.bmcl.2025.130362
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.

Keywords

Dual-target inhibitors; EGFR; HDAC3; N-benzyl-2-fluorobenzamide; Triple-negative breast cancer.

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