Small molecule Aurora kinases inhibitors

Laura Garuti*, Marinella Roberti, Giovanni Bottegoni

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

36 Citations (Scopus)

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 ATP-binding 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.

Original languageEnglish
Pages (from-to)1949-1963
Number of pages15
JournalCurrent medicinal chemistry
Volume16
Issue number16
DOIs
Publication statusPublished - 17 Aug 2009
Externally publishedYes

Keywords

  • Antitumor activity
  • ATP-competitive inhibitor
  • Aurora kinase
  • Cell cycle
  • SAR

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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