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

Authors

  • Ly-Thuy-Tram Le,

    1. Biology Laboratory, CRI-INSERM/UJF U823, Institut Albert Bonniot, Université Joseph Fourier, 38706 La Tronche (France)
    2. Permanent address: DaNang University of Technology (Vietnam)
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  • Dr. Hong-Lien Vu,

    1. Biology Laboratory, CRI-INSERM/UJF U823, Institut Albert Bonniot, Université Joseph Fourier, 38706 La Tronche (France)
    2. Permanent address: Ho Chi Minh University of Natural Sciences (Vietnam)
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  • Delphine Naud-Martin,

    1. Chemistry Laboratory, UMR 176 CNRS, Institut Curie, Bat 110 Centre Universitaire, 91405 Orsay (France)
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  • Marianne Bombled,

    1. Chemistry Laboratory, UMR 176 CNRS, Institut Curie, Bat 110 Centre Universitaire, 91405 Orsay (France)
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  • Dr. Chi-Hung Nguyen,

    Corresponding author
    1. Chemistry Laboratory, UMR 176 CNRS, Institut Curie, Bat 110 Centre Universitaire, 91405 Orsay (France)
    • Chemistry Laboratory, UMR 176 CNRS, Institut Curie, Bat 110 Centre Universitaire, 91405 Orsay (France)
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  • Dr. Annie Molla

    Corresponding author
    1. Biology Laboratory, CRI-INSERM/UJF U823, Institut Albert Bonniot, Université Joseph Fourier, 38706 La Tronche (France)
    • Biology Laboratory, CRI-INSERM/UJF U823, Institut Albert Bonniot, Université Joseph Fourier, 38706 La Tronche (France)
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Abstract

Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy. We identified benzo[e]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 benzo[e]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.

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