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Background  The JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2 V617F  inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN.    Methods  HTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2 V617F  mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2 V617F  mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay.    Results  We found that ZT55 showed a selective inhibition of a 0.031 μM IC 50  value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2 V617F  and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2 V617F -expressing HEL cell line, leading to cell cycle arrest at the G 2 /M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2 V617F  mutation.    Conclusion  These results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling.    Electronic supplementary material  The online version of this article (10.1186/s13046-019-1062-x) contains supplementary material, which is available to authorized users.

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms