期刊
BIOORGANIC CHEMISTRY
卷 118, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105486
关键词
Tubulin inhibitors; Colchicine binding site; Virtual screening; Structural optimization; Antitumor activity
资金
- Shaanxi Province's Key Project of Research and Development Plan (General Program) [2020SF205]
- National Natural Science Foundation of China [81701981]
- Innovation Capability Support Program of Shaanxi [2020TD-041]
In this study, a novel tubulin inhibitor E27 was discovered through structural optimization. E27 demonstrated significant antitumor activity, inhibition of cancer cell migration, induction of apoptosis, and cell cycle arrest.
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 mu M to 10.36 mu M, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 mu M). 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.
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