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AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders

  1. Mark A. Dawson1,2,†,
  2. Jayne E. Curry3,†,
  3. Kelly Barber2,
  4. Philip A. Beer1,2,
  5. Brent Graham3,
  6. John F. Lyons3,
  7. Caroline J. Richardson3,
  8. Mike A. Scott2,
  9. Tomoko Smyth3,
  10. Matthew S. Squires3,
  11. Neil T. Thompson3,
  12. Anthony R. Green1,2,
  13. Nicola G. Wallis3

Article first published online: 7 MAY 2010

DOI: 10.1111/j.1365-2141.2010.08175.x

Issue

British Journal of Haematology

British Journal of Haematology

Volume 150, Issue 1, pages 46–57, July 2010

Additional Information

How to Cite

Dawson, M. A., Curry, J. E., Barber, K., Beer, P. A., Graham, B., Lyons, J. F., Richardson, C. J., Scott, M. A., Smyth, T., Squires, M. S., Thompson, N. T., Green, A. R. and Wallis, N. G. (2010), AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. British Journal of Haematology, 150: 46–57. doi: 10.1111/j.1365-2141.2010.08175.x

Author Information

  1. 1

    Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge

  2. 2

    Addenbrooke’s Hospital, NHS Trust, University of Cambridge

  3. 3

    Astex Therapeutics Ltd, Cambridge Science Park, Cambridge, UK

  1. †

    MD and JC contributed equally to this manuscript.

*Nicola G. Wallis, Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. E-mail: n.wallis@astex-therapeutics.com

Publication History

  1. Issue published online: 9 JUN 2010
  2. Article first published online: 7 MAY 2010
  3. Received 8 January 2010; accepted for publication 22 February 2010

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Keywords:

  • Janus kinase 2;
  • Aurora kinase;
  • myeloproliferative disorder;
  • kinase inhibitor;
  • Jak-dependent signalling

Summary

Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.

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