A novel class of drugs - being developed by a major pharmaceutical company - targets an enzyme that helps cells divide; in cancer, this enzyme, called Aurora B, goes into overdrive, possibly leading to uncontrolled and abnormal cell divisions.
showing localisation of
exogenous Aurora proteins
The University of Manchester team in collaboration with AstraZeneca has been researching on a chemical that blocks, or inhibits, the catalytic actions of Aurora B and has proven very effective at killing cancer cells in cultures grown in the laboratory.
The Aurora kinases, a family of mitotic regulators, have received much attention 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, Aurora shows 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.
Images of culture plates
(B) showing that the Aurora B D-N
mutant mimics the effect of ZM1Aurora shows 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, Auroras may present two avenues for anti-cancer drug discovery.
One of the attractive features of Aurora B as a drug target is that cells appear to be extremely sensitive to its inhibition. Induction of the Aurora B kinase mutants alone is sufficient for a highly penetrant cell-death phenotype. By contrast, cells are relatively resistant to Aurora A inhibition: overexpression of the Aurora A kinase mutants have no apparent effect. Indeed, to expose the monopolar spindle phenotype using molecular genetic inhibition, the endogenous protein is first repressed by RNAi and then the kinase mutant is overexpressed. However, a similar phenotype can be achieved via small-molecule-mediated inhibition of Aurora A. Thus far, the longer-term consequences of this are not determined because ZM3 also inhibits Aurora B. However, it is conceivable that by preventing assembly of a bipolar spindle, a selective Aurora A inhibitor may result in activation of the SAC and prolonged mitotic arrest, which in turn may result in apoptosis. Therefore, selective Aurora A inhibitors may have potential as anti-cancer drugs in much the same way as microtubule toxins or kinesin spindle protein inhibitors (Bergnes et al., 2005). Thus, the Aurora kinases may offer two avenues for anti-cancer strategies rather than one.