Aurora B as an Anti-Cancer Drug Target
A major pharmaceutical company is developing a novel class of drugs that target an enzyme called Aurora B, which plays a role in cell division. In cancer, Aurora B becomes hyperactive, leading to uncontrolled and abnormal cell divisions.
The University of Manchester, in collaboration with AstraZeneca, has been studying a chemical compound that inhibits the catalytic actions of Aurora B. In laboratory cultures of cancer cells, this compound has demonstrated significant effectiveness in killing the cancer cells.
Aurora kinases, a family of regulators involved in cell division, have attracted attention as potential targets for anti-cancer therapies. One such inhibitor, ZM447439, has been shown to disrupt chromosome alignment, spindle checkpoint function, and cytokinesis. Cells treated with ZM447439 fail to divide during mitosis and lose viability. Since ZM447439 inhibits both Aurora A and B, researchers aimed to identify which phenotypes are specifically caused by inhibition of each kinase.
Through molecular genetic techniques, it was determined that inhibiting Aurora B kinase activity mimics the effects of ZM447439. Additionally, a new compound, more selective for Aurora B over Aurora A in vitro, produces identical phenotypes. Inhibition of Aurora B kinase activity leads to a significant reduction in cell proliferation, suggesting that Aurora B is a promising target for anti-cancer drugs. The study also explored the role of Aurora A kinase activity using molecular genetic and chemical-genetic approaches.
Cells appear to be highly sensitive to inhibition of Aurora B, as even induction of Aurora B kinase mutants alone is enough to cause cell death. On the other hand, cells show relative resistance to Aurora A inhibition. Overexpression of Aurora A kinase mutants has little effect. However, by suppressing the endogenous protein through RNA interference and then overexpressing the kinase mutant, a monopolar spindle phenotype can be observed. Small-molecule inhibitors of Aurora A can also induce this phenotype. The long-term consequences of selective Aurora A inhibition are still unclear as the currently available inhibitors also inhibit Aurora B. However, preventing the assembly of a bipolar spindle through selective Aurora A inhibition may activate the spindle assembly checkpoint (SAC) and prolong mitotic arrest, potentially leading to apoptosis. Therefore, selective Aurora A inhibitors may hold promise as anti-cancer drugs, similar to microtubule toxins or kinesin spindle protein inhibitors. The Aurora kinases offer two potential avenues for anti-cancer strategies rather than just one.
