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  3. Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance

Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance

  • Eur J Med Chem. 2025 Mar 5:285:117249. doi: 10.1016/j.ejmech.2025.117249.
Guimei Li 1,  Meng Wang 2,  Li Luo 1,  Demin Tang 1,  Nan Xu 3,  Rizhen Huang 4,  Yong Yang 3,  Guiping Chen 3,  Zhikun Liu 5,  Hengshan Wang 6,  Xiaochao Huang 7
Affiliations

Affiliations

  • 1 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China.
  • 2 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China; National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China.
  • 3 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China.
  • 4 Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
  • 5 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China. Electronic address: ytdxliuzhikun1@163.com.
  • 6 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China. Electronic address: whengshan@163.com.
  • 7 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China; National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China. Electronic address: viphuangxc@126.com.
PMID: 39823807 DOI: 10.1016/j.ejmech.2025.117249
Abstract

Nowadays, hybrid molecule with dual targets activity or effect is regarded as an effective strategy for combating the drug resistance development in Cancer therapy. Herein, novel of bifunctional conjugates targeting tubulin and MMPs inhibitors were synthesized. Among them, 15j exhibited robust Anticancer activity in vitro and in vivo, with IC50 values of 0.154-0.296 μM against four human Cancer cells and a 74.7 % (@20 mg/kg) tumor growth inhibition in vivo without obvious systemic toxicity. Mechanistic studies indicated that 15j exerted inhibitory effects on both tubulin polymerization, MMP-2 and MMP-9 activity. Moreover, 15j remarkably inhibited cell proliferation, migration and invasion, and accordingly disrupted the NF-κB signaling transduction. Furthermore, 15j effectively initiated mitochondria-dependent apoptotic pathway by causing mitochondrial dysfunction, promoting the accumulation of Reactive Oxygen Species, and inducing DNA damage. Collectively, these results demonstrated that 15j, as a tubulin/MMPs dual-targeting inhibitor, has exhibited significant potential for the lung Cancer therapy.

Keywords

Apoptosis; Chalcone; Lung cancer; MMPs; Tubulin.

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