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

Constitutive activation of Janus kinase (Jak) 2 is easily the most prevalent pathogenic event noticed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove useful for their management. Inhibition from the Aurora kinases has additionally shown to be a highly effective therapeutic strategy in many haematological malignancies. AT9283 is really a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and it is presently being evaluated in numerous studies. To research the therapeutic potential of AT9283 within the MPD we studied its activity in many Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines in addition to inhibiting the development of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also shown significant therapeutic potential in vivo within an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was noticed in the model systems used, indicating a dual mechanism of action. Our results claim that AT9283 can be a valuable therapy in patients with MPD which the twin inhibition of Jak2 and also the Aurora kinases might offer AT9283 combinatorial effectiveness in treating these illnesses.