BMS-911543是一种有效的，选择性的JAK2抑制剂，IC50为1.1 nM，比作用于JAK1， JAK3和TYK2选择性分别高约350， 75和65倍。Phase 1/2。BMS-911543是一种吡咯并吡啶类小分子抑制剂。BMS-911543对JAK1，JAK2和JAK3的解离常数拓展了研究结果，对JAK2具有更广的选择性，K_i值分别为1114, 0.48和357 nm。BMS-911543除了抑制JAK家族外，还最有效抑制Src家族成员，Lyn (IC50=300 nm), 和 c-FMS受体酪氨酸激酶 (IC50=450 nm), 这两者敏感性都低于JAK2 (>250倍)。

>98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

Ethanol ：21 mg/mL (48.6 mM)

DMSO ：34 mg/mL (78.6 mM)

JAK2 ,SET-2 ,TYK2 ,JAK3

BMS-911543 shows potent antiproliferative activity in the SET-2 as well as BaF3-V617F engineered cell lines (both dependent upon JAK2 pathway), with IC50 values of 60 and 70 nM, respectively. The antiproliferative activity of BMS-911543 in SET-2 and BaF3-V617F cells correlates with similar activity on constitutively active pSTAT5 (IC50 80 and 65 nM, respectively). In contrast, non-JAK2-dependent cell lines (A549, MDA-MB-231, MiaPaCa-2) are significantly less sensitive to the inhibitor treatment. The excellent biochemical selectivity versus JAK1/3 translates to good cellular and functional selectivity in an IL-2 mediated T-cell proliferation assay (IC50 990 nM). Also, cell lines that rely on other JAK family members, including CTLL2 and parental BaF3 cells stimulated with IL-3, shows weak antiproliferative activity for BMS-911543 (IC50 2.9 and 3.5 μM, respectively).

BMS-911543 suppresses the pSTAT5 levels (mediated by wild type JAK2) relative to vehicle control when stimulated with thrombopoetin (TPO) in a mouse pharmacodynamic model. The responses are dose dependent and results in nearly complete normalization of pSTAT5 levels for 18 h at the highest oral dose of 30 mg/kg. At an intermediate 10 mg/kg oral dose, ∼65% reduction is observed up to 18 h, whereas at the 5 mg/kg dose, approximately 50% reduction in pSTAT5 for 8 h is achieved. Observed pSTAT5 reductions correlates with exposures of BMS-911543, with AUC0–8h values of 23, 41, and 109 μM·h, respectively, for dose levels of 5, 10, and 30 mg/kg. In addition, BMS-911543 demonstrates a potent and sustained (2 mg/kg up to 7 h) PD effect in blocking pSTAT5 formation in mice grafted with human SET-2 cells harboring JAK2-V617F mutation. The JPolute oral bioavailability in solution is >50% in mice, rats, dogs, and monkeys. In addition, the JPorption of BMS-911543 is not significantly impacted by particle dissolution (suspension formulation), with a relative bioavailability (vs solution) of ∼60% in rats and ∼100% in dogs.