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Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

Leukemia volume 24, pages 671–678 (2010)Cite this article

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Abstract

Aurora kinases are a family of protein kinases that have a key role in multiple stages of mitosis. Over-expression of Aurora kinases, particularly Aurora A, has been demonstrated in a number of solid tumors and hematological malignancies. Not surprisingly, these serine/threonine kinases have become attractive small molecule targets for cancer therapeutics, with several inhibitors currently in early-phase clinical trials. A small number of compounds developed to date are highly selective for either Aurora A or Aurora B, while the majority inhibit both Aurora A and Aurora B; many of these compounds exhibit ‘off-target’ inhibition of kinases such as ABL, JAK2 and FLT3. It is currently unclear whether the therapeutic activity of these compounds in leukemia is primarily due to selective Aurora or multi-kinase inhibition. The most promising application for Aurora kinase inhibitors to date appears to be in FLT3-mutated acute myeloid leukemia (AML) and imatinib-resistant chronic myeloid leukemia/Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, particularly when caused by the T315I mutation. Here we review the growing body of evidence supporting the use of Aurora kinase inhibitors as effective agents for AML and Ph+ leukemias.

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Acknowledgements

We are grateful to Amir Faisal (Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK) for kindly providing the immunofluorescent images in Figure 1. Andrew Moore is supported by Cancer Research UK and in part by a New Investigator Scholarship awarded by the Haematology Society of Australia and New Zealand. Spiros Linardopoulos is supported by Cancer Research UK and Breakthrough Breast Cancer. Julian Blagg and Andrew Pearson are supported by Cancer Research UK. We acknowledge NHS funding to the NIHR Biomedical Research Centre.

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  1. Section of Paediatric Oncology, The Institute of Cancer Research, Sutton, UK

    A S Moore & A D J Pearson

  2. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK

    A S Moore, J Blagg & S Linardopoulos

  3. Paediatric Oncology, Royal Marsden NHS Foundation Trust, Sutton, UK

    A S Moore & A D J Pearson

  4. Breakthrough Breast Cancer Research Centre, London, UK

    S Linardopoulos

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The authors declare the following relevant conflicts of interest. The authors are employees of The Institute of Cancer Research, which has a commercial interest in drug development programs (see www.icr.ac.uk). Please note that all authors who are, or have been, employed by The Institute of Cancer Research are subject to a ‘Rewards to Inventors Scheme’, which may reward contributors to a program that is subsequently licensed. The authors have or have had direct or indirect commercial interactions with Astex Pharmaceuticals and Astra Zeneca. Julian Blagg is a stockholder of Pfizer.

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Moore, A., Blagg, J., Linardopoulos, S. et al. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 24, 671–678 (2010). https://doi.org/10.1038/leu.2010.15

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