| 生化机理 |
Description:
IC50 Value: 0.48 ± 0.02 nM (JAK2 JH1); 0.58 ± 0.03 nM (FL JAK2 wt) [1]
BSK-805, a novel substituted quinoxaline, is a potent inhibitior of JAK2(V617F) and JAK2 wild-type enzymes, BSK-805 acts in an ATP-competitive manner.
in vitro: NVP-BSK805 was found to potently inhibit JAK2, whereas displaying more than 20-fold selectivity towards JAK1, JAK3, and TYK2. In proliferation assays with most of these cellular models, NVP-BSK805 exhibited half-maximal growth inhibition (GI50) at concentrations <100 nmol/L. In K-562 cells, NVP-BSK805 suppressed growth with a GI50 value of ?1.5 μmol/L. In CMK cells, the GI50 value of NVP-BSK805 was in the range of 2 μmol/L, seemingly consistent with the JAK family selectivity observed in biochemical assays [1]. NVP-BSK805 blunts constitutive STAT5 phosphorylation in JAK2V617F mutant cell lines, reduces Bcl-xL levels and blocks cell proliferation with concomitant induction of cell death [2].
in vivo: To test the ability of NVP-BSK805 to modulate JAK2V617F/STAT5 signaling in the spleen, mice were given 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 cause prolonged suppression of STAT5 phosphorylation in spleen extracts, reducing levels by nearly half relative to vehicle-treated controls at the 6- and 12-hour time points. To assess the ability of the compound to control JAK2V617F-dependent leukemic disease, oral daily dosing of NVP-BSK805 at 50 or 150 mg/kg was initiated on day 5 post-Ba/F3 cell injection, 1 day after leukemic burden was evident following bioluminescence measurements. On day 9, whole-body bioluminescence readings indicated that compound-treated mice had a significantly lower leukemic load as compared with the vehicle control group [1].
Toxicity: N/A
Clinical trial: N/A
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