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

Mark A Dawson (1) , Jayne E Curry (2) , Kelly Barber (3) , Philip A Beer (4) , Brent Graham (2) , John F Lyons (5) , Caroline J Richardson (2) , Mike A Scott (6) , Tomoko Smyth (5) , Matthew S Squires (5) , Neil T Thompson (2) , a R Green (7) , Nicola G Wallis (8)

1 Division of Transfusion Medicine
2 Biology
3 Addenbrooke's Hospital
4 Haematology
5 Translational Biology
6 Haematology
7 Department of Haematology
8 Biology

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, which 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 a 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.

Mots clés: Medicine

Mark A Dawson, Jayne E Curry, Kelly Barber, Philip A Beer, Brent Graham, et al.. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. British Journal of Haematology, 2010, ⟨10.1111/j.1365-2141.2010.08175.x⟩. ⟨hal-00552590⟩