Validating Aurora B as an anti-cancer drug target.
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.
Girdler
Fiona
F
Faculty of Life Sciences, Michael Smith Building, Oxford Road, University of Manchester, Manchester, M13 9PT, UK.
Gascoigne
Karen E
KE
Eyers
Patrick A
PA
Hartmuth
Sonya
S
Crafter
Claire
C
Foote
Kevin M
KM
Keen
Nicholas J
NJ
Taylor
Stephen S
SS
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D016764:Cell Polarity; D049109:Cell Proliferation; D002470:Cell Survival; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000628:therapy*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism
C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D000970:Antineoplastic Agents; D001549:Benzamides; D011799:Quinazolines; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases