2. Academic Validation
  3. Novel imidazo[1,2-a]pyridine-based tubulin polymerization inhibitors: Structure-activity relationships and anti-tumor immune potentiation

Novel imidazo[1,2-a]pyridine-based tubulin polymerization inhibitors: Structure-activity relationships and anti-tumor immune potentiation

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118356. doi: 10.1016/j.ejmech.2025.118356.
Binbin Cheng 1,  Chao Li 2,  Xixiang Yang 3,  Yinrong Wu 3,  Yong Ruan 3,  Yichang Ren 3,  Zhenhong Su 4,  Shanhe Wan 5,  Xin Li 6,  Dulin Kong 7,  Jianjun Chen 8
Affiliations

Affiliations

  • 1 School of Medicine, Hubei Polytechnic University, Huangshi, 435003, China; Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang, 323000, China.
  • 2 Department of Oncology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 4 School of Medicine, Hubei Polytechnic University, Huangshi, 435003, China. Electronic address: [email protected].
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 6 Shenzhen Key Laboratory of Viral Oncology, Shenzhen Hospital of Southern Medical University, Guangdong, China. Electronic address: [email protected].
  • 7 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, International Joint Research Center of Human-Machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, School of Pharmaceutical Sciences, Hainan Medical University, Haikou, 571199, China. Electronic address: [email protected].
  • 8 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 41218519 DOI: 10.1016/j.ejmech.2025.118356
Abstract

Building on our previous research, a series of novel imidazo[1,2-a]pyridine derivatives were rationally designed and synthesized as tubulin polymerization inhibitors. Among these analogues, compound 5b exhibited the strongest antiproliferative activity against Jurkat, B16-F10, HCT116, and MDA-MB-231 cells, with IC50 values of 60 nM, 380 nM, 138 nM, and 1.054 μM, respectively. Further functional assays revealed that 5b can effectively suppress the migration and colony-forming capacity of B16-F10 cells. Mechanistically, compound 5b induced Apoptosis and arrested the cell cycle in the G2/M phase by inhibiting tubulin polymerization. Molecular docking simulations revealed that 5b efficiently binds to the colchicine-binding pocket of tubulin, providing a structural basis for its activity. In vivo, compound 5b (10 mg/kg) demonstrated potent anti-tumor efficacy in a melanoma model without obvious systemic toxicity. Notably, 5b markedly potentiated the in vivo anti-tumor immune response through its combination with a PD-L1 monoclonal antibody (mAb), as evidenced by increased infiltration of cytotoxic CD8+ effector T cells in tumor tissues. Collectively, these findings identify 5b as a promising tubulin polymerization inhibitor with immune-modulatory potential, meriting further investigation.

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