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

Guimei Li; Meng Wang; Li Luo; Demin Tang; Nan Xu; Rizhen Huang; Yong Yang; Guiping Chen; Zhikun Liu; Hengshan Wang; Xiaochao Huang

doi:10.1016/j.ejmech.2025.117249

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

Eur J Med Chem. 2025 Jan 9:285:117249. doi: 10.1016/j.ejmech.2025.117249. Online ahead of print.

Authors

Guimei Li¹, Meng Wang², Li Luo¹, Demin Tang¹, Nan Xu³, Rizhen Huang⁴, Yong Yang³, Guiping Chen³, Zhikun Liu⁵, Hengshan Wang⁶, Xiaochao Huang⁷

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: [email protected].
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: [email protected].
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: [email protected].

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.