NVP-BSK805 is a potent and selective ATP-competitive JAK2 inhibitor with IC50 of 0.5 nM; >20-fold selectivity towards JAK1, JAK3 and TYK2.

NVP-BSK805 is found to potently inhibit JAK2, whereas displaying more than 20-fold selectivity towards JAK1, JAK3, and TYK2. NVP-BSK805 causes half-maximal inhibition of full-length JAK2V617F and JAK2 wild-type enzymes at 0.5 nM. NVP-BSK805 blocks the growth of JAK2V617F cells (Ba/F3) and induces apoptosis with a GI50 at concentrations ＜100 nM. As constitutive STAT5 phosphorylation in dependent on JAK2, NVP-BSK805 is found to potently suppress STAT5 phophorylation at ≥ 100 nM concentrations in the JAK2 V617F -mutant cell lines, like MB-02. Incubation of SET-2 cells with 150 nM and 1μM of NVP-BSK805, which corresponds to concentration yielding 75% and 95% growth inhibition, respectively, for 24, 48, and 72 hours lead to concentration- and time- dependent induction of apoptosis. These results are evidenced by the detection of cleaved PARP, reduced Bcl-xL expression, and a strong increase in the number of cells with less than 2N DNA content. NVP-BSK805 triggered cell death requires activation of caspase cascades and is overcome by caspase inhibition in both SET-2 and MB-02 cells. NVP-BSK805 modulates the post-translational modification of Bim and levels of Mcl-1 in JAK2V617F cells, SET-2 and MB-02 cells

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