NVP-BSK805 is a potent and selective quinoxaline JAK2 inhibitor with IC50 of 0.48, 0.56 and 0.58 nM for JAK2 JH1, FL JAK V617F and FL JAK2 wt, respectively. NVP-BSK805 displays more than 20-fold selectivity over the other JAK family members and more than 100-fold selectivity over a panel of kinases in vitro. NVP-BSK805 has less inhibitory activity for JAK1 JH1 (IC50=61.6 nM) and JAK3 JH1 (IC50=18.7 nM). In proliferation assays with most of Ba/F3-based models, NVP-BSK805 blocks the growth of JAKV617F cells and induces apoptosis. NVP-BSK805 exhibited half-maximal growth inhibition (GI50) at concentrations <100 nM. NVP-BSK805 also suppresses JAK2V617F-driven leukemic disease in vivo. Mice were administered 150 mg/kg orally of NVP-BSK805 on day 9 post-Ba/F3 cell injection, when most of the spleen consisted of Ba/F3 cells. NVP-BSK805 was found to give rise to prolonged prevention of STAT5 phosphorylation in spleen extracts, decreasing levels by nearly half relative to vehicle-treated controls at the 6- and 12- hour time points. NVP-BSK805 be suggested to be a suitable tool compound to explore combinations of JAK2 inhibitors with other agents in preclinical models of myeloproliferative-like disease. [1]
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