Identification of an indol-based multi-target kinase inhibitor through phenotype screening and target fishing using inverse virtual screening approach

Abstract A series of 1,3,5-substituted indole derivatives was prepared to explore the anti-proliferative activity against a panel of human tumour cell lines. A 5-carboxamide derivative ( 27 ) emerged as the most potent compound of this series, inhibiting the HeLa cell growth at sub-micromolar concentrations. Target fishing of 27 using a combination of inverse virtual screening (IVS) approach and ligand-based shape similarity study identified the top-ranked targets for 27 as belonging to kinome. These results were further confirmed by in vitro binding assays, leading to the identification of 27 as multi-target kinase inhibitor. The compound 27 was further characterized for its antiproliferative activity by in cell studies, showing a mechanism of action involving modification of the cell cycle, increase in ROS release and caspase 3-expression and decrease in ERK expression.