2. Academic Validation
  3. Discovery of novel coumarin-sulfonates as tubulin polymerization inhibitors targeting the colchicine-binding site with potent anticancer activities

Discovery of novel coumarin-sulfonates as tubulin polymerization inhibitors targeting the colchicine-binding site with potent anticancer activities

  • Bioorg Med Chem Lett. 2025 Sep 1:125-126:130284. doi: 10.1016/j.bmcl.2025.130284.
Dan Zhao 1,  Ji Wu 2,  Jing-Sai Song 3,  Bing-Bing Chen 4,  Yi-Fei Du 4,  Meng-Bo Wu 5,  Jin-Bo Niu 3,  Jian Song 4,  Yan Xu 6,  Sai-Yang Zhang 7
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 2 School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
  • 3 The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 4 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 5 Henan Vocational University of Science and Technology, ZhouKou 466001, China.
  • 6 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: xuyan6@zzu.edu.cn.
  • 7 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: saiyangz@zzu.edu.cn.
PMID: 40393635 DOI: 10.1016/j.bmcl.2025.130284
Abstract

A series of novel coumarin-sulfonate derivatives as potent microtubule-targeting inhibitors was constructed utilizing a molecular hybridization strategy, and their antiproliferative activities were evaluated against MGC-803, KYSE450 and HCT-116 Cancer cell lines. Among them, compound C20 exhibited potent antiproliferative effects on KYSE450 cells (IC50 = 0.36 μM) and EC-109 cells (IC50 = 0.63 μM). Mechanistic studies revealed that C20 could occupied the colchicine-binding site to suppress tubulin polymerization, thereby disrupting the microtubule network integrity in KYSE450 and EC-109 cells. Notably, C20 activated the Hippo signaling pathway and downregulated the expression of the oncogenic protein YAP in KYSE450 and EC-109 cells. In addition, C20 effectively suppressed colony formation, induced G2/M phase cell cycle arrest, and promoted Apoptosis in KYSE450 and EC-109 cells. These effects of cell Apoptosis were correlated with the modulation of Apoptosis related proteins cleaved PARP and cleaved Caspase3/7 level. Collectively, these findings elucidated that C20, as a tubulin polymerization inhibitor, could destroy microtubule dynamics and activate the Hippo signaling pathway, thereby exhibiting strong anti-esophageal Cancer activities.

Keywords

Antiproliferative activities; Colchicine-binding site; Coumarin; Sulfonate; Tubulin.

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