Validating Aurora B as an anti-cancer drug target

Fiona Girdler, Karen E. Gascoigne, Patrick A. Eyers, Sonya Hartmuth, Claire Crafter, Kevin M. Foote, Nicholas J. Keen, Stephen S. Taylor

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.
    Original languageEnglish
    Pages (from-to)3664-3675
    Number of pages11
    JournalJournal of Cell Science
    Volume119
    Issue number17
    DOIs
    Publication statusPublished - 1 Sep 2006

    Keywords

    • Chemical genetics
    • Drug-resistance
    • Hesperadin
    • VX-680
    • ZM447439

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