Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressing Jak2V617F.
Bottom Line: CEP701 shows a unique combination of both activities which is not found in other compounds also targeting Jak2.CEP701 demonstrated a combined suppression of both colony types.Moreover, we show that combined application of a Janus and an Aurora kinase inhibitor recapitulated the effect observed for CEP701 but might allow for more flexibility in combining both activities in clinical settings, e.g. in the treatment of myeloproliferative neoplasms.
Affiliation: Life Sciences Research Unit - Signal Transduction Laboratory, University of Luxembourg, Luxembourg, Luxembourg.Show MeSH
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Mentions: Human erythroleukaemia cells endogenously expressing the constitutively active mutant Jak2V617F were used to assess the effect of the compounds on proliferation (Fig. 1A). Furthermore, the actual capacity of the different compounds to inhibit Jaks was evaluated by monitoring phosphorylation of STAT5, a direct target of Jak2V617F which is constitutively phosphorylated in HEL cells (Fig. 1B and Figure S2C). Several compounds such as AT9283, CEP701, TG101209 and JI1 reduced proliferation of HEL cells very effectively and at the same time strongly reduced phosphorylation of STAT5 at a concentration of 0.5 μM. TG101348 and CYT387 showed the same effects but were less efficient. Six of the 12 compounds (VX680, Sunitinib, WP1066, AG490, LFM-A13 and JNJ7706621) did not inhibit the phosphorylation of STAT5 up to concentrations of 5 μM (Fig. 1B and Figure S2C). AG490, LFM-A13 and JNJ7706621 neither affected cell growth at concentrations up to 1 μM (data not shown). However, Sunitinib and WP1066 had a moderate effect on HEL cell growth, while VX680 very efficiently inhibited HEL cell growth already at 0.3 μM.
Affiliation: Life Sciences Research Unit - Signal Transduction Laboratory, University of Luxembourg, Luxembourg, Luxembourg.