Aurora kinase targeted therapeutics in oncology: past, present and future

Abstract

Aurora A, B and C are a family of serine-threonine protein kinases that regulate distinct functions of the mitotic phase of the cell cycle. All three Auroras are overexpressed in human cancers with an associated polyploid phenotype. Crystal structures of Aurora A or B with bound small molecular inhibitors have provided detailed insight of the active site, mode of binding and hotspots for developing resistance through point mutations. Structural studies have aided fragment-based rational drug discovery of Aurora inhibitors, including compounds specific for Aurora A or B. Aurora inhibitors have excellent antitumor activity in rodent models of cancer. At present, Aurora inhibitors are being evaluated in Phase I trials. The future holds promise for rational combinations in both solid and hematological malignancies.

Keywords::

• aneuploidy
• Aurora kinase
• cancer
• cell cycle
• mitotic phase
• small molecular inhibitor

Acknowledgements

The authors wish to thank S Narayan and K Shakalya, Arizona Cancer Center, Tucson, Arizona 85724 for their technical assistance in molecular graphics.

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