Exploring the molecular mechanisms of a small molecule inhibitor of Aurora kinases

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Aurora kinases have been found to be over-expressed in many human tumours making them attractive candidates for anticancer therapy. Using a biochemical assay, we have identified a potent small molecule Aurora kinase inhibitor selective for the three Aurora kinase family members Aurora A, B & C. The compound (PHA-680632) shows the expected cellular phenotypes in mitosis, based on the molecular mechanism of action. However, a differential response of cancer cells compared to normal cells has been observed: Cancer cells typically respond by entering endo-reduplication and subsequent mitotic catastrophe, whereas normal cells (normal human dermal fibroblasts) are reversibly blocked in the G2/M phase of the cell cycle. This difference might be based on an impaired checkpoint response in tumor cells. In vivo, treatment with PHA-680632 resulted in tumor growth inhibition in different tumor models and is accompanied by biomarker modulation such as inhibition of phosphorylation of histone H3 or BubR1. Our data support the concept that inhibition of Aurora kinases represents a promising approach for anti-cancer therapy.