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  3. Discovery of quinoxaline-chalcone derivatives as covalent colchicine binding site inhibitors for breast and fibrosarcoma treatment

Discovery of quinoxaline-chalcone derivatives as covalent colchicine binding site inhibitors for breast and fibrosarcoma treatment

  • Eur J Med Chem. 2026 Jun 5:310:118786. doi: 10.1016/j.ejmech.2026.118786.
Lu Lu 1,  Ziyu Wang 1,  Lige Liu 2,  Xiaoqing Geng 1,  Haowen Zhang 1,  Shaochi Wang 3,  Tingting Liang 4,  Yahong Zhang 5,  Jianhong Wang 6
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan Province, 475004, China.
  • 2 Pharmacy Department of No. 988 Hospital of Logistic Support Force, Zhengzhou, Henan Province, 450052, China.
  • 3 Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, China.
  • 4 Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan Province, 475004, China; The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan Province, 450000, China; State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng, Henan Province, 475004, China. Electronic address: liangting910710@126.com.
  • 5 Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan Province, 475004, China; State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng, Henan Province, 475004, China. Electronic address: zhangyahong131@163.com.
  • 6 Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan Province, 475004, China. Electronic address: jhworg@126.com.
PMID: 41889031 DOI: 10.1016/j.ejmech.2026.118786
Abstract

Targeting the colchicine binding site is an attractive pharmacological strategy to overcome the multidrug resistance microtubule-targeting agents are faced with. Herein, a series of novel covalent quinoxaline-chalcone derivatives were rationally designed using pharmacophore fusion with S-Ⅳ-25 as lead compound. All obtained target compounds were evaluated for their inhibitory activities and the structure-activity relationships were summarized, leading to the identification of a potent colchicine binding site inhibitor 10v. 10v showed the most potent antiproliferative activity against three Cancer cell lines (HT-1080, MCF-7, MDA-MB-231), and further inhibited colony formation and migration. Mechanistic studies demonstrated that 10v inhibited tubulin polymerization and disrupted microtubule network via covalent binding to the colchicine binding site of tubulin. Further mechanistic assays revealed 10v arrested cell cycle at G2/M phase and induced cell Apoptosis through mitochondrial-mediated pathway. More importantly, 10v exhibited antiproliferative activity against MCF-7/ADM cells via covalent binding and P-gp inhibition. Meanwhile, molecular docking result suggested 10v occupied colchicine binding site and formed covalent binding with β-Cys239. Finally, in vivo study indicated 10v showed better in vivo antitumor efficacy than paclitaxel with acceptable safety.

Keywords

Antitumor efficacy; Colchicine binding site; Covalent inhibitor; Quinoxaline-chalcone derivatives; Tubulin polymerization inhibition.

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