Small Molecule Aurora Kinases Inhibitors

Laura      Garuti; Marinella      Roberti; Giovanni      Bottegoni

Abstract

Aurora kinases represent one of the emerging targets in oncology drug discovery. These kinases play important role in centrosome maturation, chromosome separation and cytokinesis. They are overexpressed in a broad range of tumor cell lines and human primary tumors; thus, their inhibition may open up new opportunities to develop novel anti-cancer agents. A range of potent small molecule inhibitors of Aurora kinases have been identified and found to have antitumor activity. Some of these agents are undergoing evaluation in clinical trials. Most synthetic Aurora kinase inhibitors are ATP-competitive, which makes selectivity a potential problem. However, despite the high sequence similarity in the ATPbinding pocket, several compounds are very specific in their targets. The ability of the inhibitors to extend their binding to regions adjacent to the ATP pocket, including the hydrophobic back pocket, contributes to the selectivity, since structural differences can be found in these regions. A common structural feature of the inhibitors is a planar heterocyclic ring system able to occupy the adenino-binding region and to mimic the adenine-kinase interactions, by making backbone hydrogen bond interactions, but also by extensive hydrophobic contacts within this part of the pocket. In this review we would like to analyse the main inhibitors, focusing on chemical structures, SAR and biological properties. The specific targeting of these kinases could result in highly active drugs with minimal collateral host toxicity. Moreover, the combination of Aurora inhibitors with other chemotherapeutic agents may open new opportunities in cancer chemotherapy.

Keywords: Aurora kinase, cell cycle, SAR, antitumor activity, ATP-competitive inhibitor