Hydrosoluble Benzo[e]pyridoindolones as Potent Inhibitors of Aurora Kinases

Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy. We identified benzoe]pyridoindoles (BePI) as powerful aurora kinase inhibitors. Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays. New BePI molecules were synthesized, and a structure–activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound. Tetracyclic BePI derivatives are characterized by a particular curved shape, and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase B inhibition. New hydrosoluble benzoe]pyridoindolones were subsequently designed, and their efficacy was tested by a combination of cell‐cycle analysis and time‐lapse experiments in live cells. The most active BePI derivative, 13 b , inhibited the cell cycle, drove cells to polyploidy, and eventually induced apoptosis. It exhibited high antiproliferative activity in HeLa cells with an IC₅₀ value of 63 nM . Relative to compounds tested in clinical trials, this antiproliferative potency places 13 b among the top 10 aurora kinase inhibitors. Our results justify further in vivo evaluation in preclinical animal models of cancer.