2. Academic Validation
  3. Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation

Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation

  • Bioorg Chem. 2022 Jan;118:105486. doi: 10.1016/j.bioorg.2021.105486.
Wei Liu 1,  Hairui Jia 2,  Minghao Guan 3,  Minxuan Cui 3,  Zhuxuan Lan 3,  Youyou He 3,  Zhongjie Guo 3,  Ru Jiang 3,  Guoqiang Dong 4,  Shengzheng Wang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi Province, China.
  • 2 Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi Province, China.
  • 3 Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
  • 5 Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China. Electronic address: [email protected].
PMID: 34801948 DOI: 10.1016/j.bioorg.2021.105486
Abstract

The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC50 values ranging from 7.81 μM to 10.36 μM, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 μM). It significantly inhibited Cancer cell migration and invasion, induced cell Apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.

Keywords

Antitumor activity; Colchicine binding site; Structural optimization; Tubulin inhibitors; Virtual screening.

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