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Annals of Oncology 2007 18(Supplement 6):vi47-vi52; doi:10.1093/annonc/mdm224
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© 2007 European Society for Medical Oncology

small molecule kinasi inhibitors

The role of Aurora-A inhibitors in cancer therapy

V Agnese1,{dagger}, V Bazan1,{dagger}, FP Fiorentino1, D Fanale1, G Badalamenti1, G Colucci2, V Adamo3, D Santini4 and A Russo1,*

1 Section of Medical Oncology, Department of Surgery and Oncology, Università di Palermo, Palermo
2 Division of Medical Oncology, National Institute of Oncology, Bari
3 Department of Human Pathology, Medical Oncology and Integrated Therapies Unit, Universitary Policlinico "G.Martino" of Messina, Messina
4 Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy

* Correspondence to: Antonio Russo, MD. Section of Medical Oncology, Department of Surgery and Oncology, Università di Palermo, Via del Vespro 127, 90127 Palermo, Italy. Tel: +39-091-6552500; Fax: +39-091-6554529; E-mail: lab-oncobiologia{at}usa.net

Recently, new chemotherapy agents which target the non-structural components of mitosis have been developed. An important protein involved in several mitotic phases is the Aurora-A protein. By means of the phosphorylation of different substrates, Aurora-A regulates the correct development of the various phases of mitosis. The kinase activity of this protein makes Aurora-A an excellent candidate as an oncogene. The first data of Aurora-A involvement in cancer regarded the identification of Aurora-A overexpression in primary breast and colon tumour samples. With regard to the predictive role of Aurora-A, it has been shown that its overexpression disrupts the spindle checkpoint activated by paclitaxel (Taxol) or nocodazole treatment, thus inducing the cells to become resistant to these drugs. The development therefore of small molecules with an Aurora-A inhibition function may make it possible to reduce or block the oncogenic activity of Aurora-A and in addition may improve the survival of oncological patients showing resistance to paclitaxel or nocodazole treatment. Three novel Aurora kinase inhibitors have recently been described—Hesperadin, ZM447439 and VX-680. All these three drugs have been designed to target the ATP-binding site of Aurora kinase, so they inhibit all three Aurora kinase family members showing a similar phenotype when tested in cell-based assays. Among these three different molecules, VX-680 has shown promising results in in vitro and in vivo studies. In conclusion, it is clear that we are entering a new era in anti-mitotic therapy with the identification and now clinical translation of new targets in mitosis beyond tubulin but many questions remain with regard to Aurora function.

Key words: Aurora-A, cancer treatment, kinase inhibitor, mitosis, small molecule

{dagger} Both authors have contributed equally to this work.


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