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

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.