Fedratinib hydrochloride hydrate (TG-101348 hydrochloride hydrate) is a potent, selective, ATP-competitive and orally active JAK2 inhibitor with IC50s of 3 nM for both JAK2 and JAK2V617F kinase. Fedratinib hydrochloride hydrate shows 35- and 334-fold selectivity over JAK1 and JAK3, respectively. Fedratinib hydrochloride hydrate induces cancer cell apoptosis and has the potential for myeloproliferative disorders research.
The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease (MPD), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. Fedratinib hydrochloride hydrate is a potent, selective and ATP-competitive JAK2 inhibitor with IC50s of 3 nM for both JAK2 and JAK2V617F kinase. Fedratinib inhibited proliferation of a human erythroblast leukemia (HEL) cell line that harbors the JAK2V617F mutation, as well as a murine pro-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F), with an IC50 value of approximately 300 nM for either line. Proliferation of parental Ba/F3 cells was inhibited to a comparable level, with an IC50 value of ~420 nM. Furthermore, exposure of these cells to fedratinib (0.1, 0.3, 1, 3, and 10 μM) reduced STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. Moreover, fedratinib (0.1, 0.3, 1, 3, and 10 μM) induced apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. In vivo, fedratinib (60-120 mg/kg; oral gavage; twice daily; for 42 days) caused a dose-dependent reduction in polycythemia and splenomegaly of treated C57Bl/6 mice[1].
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