Discovery and structural-activity relationship of N-benzyl-2-fluorobenzamides as EGFR/HDAC3 dual-target inhibitors for the treatment of triple-negative breast cancer.
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| 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. |
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| Authors: | Ge GH; 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., Guo S; 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., Li TT; 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., Wang YP; 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., Liu LR; 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., Yu WH; 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., Hu H; 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., Zheng YM; 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., Yan JH; 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., Sun YH; 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., Liang JW; 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., Meng FH; 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., Zhang TJ; 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. |
| Source: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2025 Dec 01; Vol. 128, pp. 130362. Date of Electronic Publication: 2025 Aug 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Ltd Original Publication: Oxford ; New York : Pergamon Press, c1991- |
| MeSH Terms: | Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/pathology , Triple Negative Breast Neoplasms*/metabolism , ErbB Receptors*/antagonists & inhibitors , ErbB Receptors*/metabolism , Histone Deacetylases*/metabolism , Histone Deacetylase Inhibitors*/chemistry , Histone Deacetylase Inhibitors*/pharmacology , Histone Deacetylase Inhibitors*/chemical synthesis , Histone Deacetylase Inhibitors*/therapeutic use , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/therapeutic use , Benzamides*/chemistry , Benzamides*/pharmacology , Benzamides*/chemical synthesis , Benzamides*/therapeutic use , Drug Discovery*, Humans ; Structure-Activity Relationship ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Female ; Animals ; Drug Screening Assays, Antitumor ; Apoptosis/drug effects ; Mice ; Molecular Structure ; Dose-Response Relationship, Drug ; Cell Movement/drug effects |
| Abstract: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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 2+ 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. (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
| Contributed Indexing: | Keywords: Dual-target inhibitors; EGFR; HDAC3; N-benzyl-2-fluorobenzamide; Triple-negative breast cancer |
| Substance Nomenclature: | EC 2.7.10.1 (ErbB Receptors) EC 3.5.1.98 (Histone Deacetylases) EC 3.5.1.98 (histone deacetylase 3) 0 (Histone Deacetylase Inhibitors) 0 (Antineoplastic Agents) 0 (Benzamides) EC 2.7.10.1 (EGFR protein, human) |
| Entry Date(s): | Date Created: 20250805 Date Completed: 20250824 Latest Revision: 20250826 |
| Update Code: | 20250827 |
| DOI: | 10.1016/j.bmcl.2025.130362 |
| PMID: | 40763846 |
| Database: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />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.<br /> (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
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| ISSN: | 1464-3405 |
| DOI: | 10.1016/j.bmcl.2025.130362 |