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NVP-BSK805 2HCl

现货
Catalog No.
A4148
JAK2抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,700.00
现货
10mg
¥ 2,300.00
现货
50mg
¥ 5,900.00
现货
200mg
¥ 16,900.00
现货

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Background

NVP-BSK805 2HCl is a potent and selective ATP-competitive inhibitor of JAK2 [1].

Janus kinase 2 (JAK2), a non-receptor tyrosine kinase, is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptorfamily, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors[2].

In vitro: NVP-BSK805 potently inhibited JAK2, displaying more than 20-fold selectivity towards JAK1, JAK3, and TYK2. In an internal kinase panel, NVP-BSK805 showed potent inhibition of JAK2, along with good selectivity towards the other three JAK family members, indicating the fairly selectivity against other kinases. NVP-BSK805 is an ATP-competitive inhibitor with the Ki values of 0.43 ± 0.02 nmol/L. In Ba/F3 cell-based assays of JAK2V617F dependency and a panel of JAK2V617F-bearing acute myeloid leukemia cell lines derived from patients with a history of cMPNs, NVP-BSK805 exhibited half-maximal growth inhibition (GI50) at concentrations < 100 nmol/L. In K-562 cells, NVP-BSK805 suppressed growth with the GI50 value of 1.5 μmol/L. In CMK cells, the GI50value of NVP-BSK805 was about 2 μmol/L. Incubation of SET-2 cells with 150 nM and 1 μM 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[1]. In both SET-2 and MB-02 cells,NVP-BSK805 triggered cell death required activation of caspase cascades and was overcome by caspase inhibition. NVP-BSK805 modulated the post-translational modification of Bim and levels of Mcl-1 in JAK2V617F cells, SET-2 and MB-02 cells[3].

In vivo: Oral bioavailability of NVP-BSK805 in mice was estimated to be 45%, while 50% in rats. In a Ba/F3 JAK2V617F cell–driven mouse model, Oral administration of NVP-BSK805 (150 mg/kg) suppressed STAT5 phosphorylation, splenomegaly, and leukemic cell spreading. In BALB/c mice, NVP-BSK805 suppressedrhEpo-induced STAT5 phosphorylation as well as rhEpo-mediated polycythemia and splenomegaly at doses of 25, 50, and 100 mg/kg orally [1].

References:
[1] Baffert F, Régnier C H, De Pover A, et al.  Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805[J]. Molecular cancer therapeutics, 2010, 9(7): 1945-1955.
[2] Bole-Feysot C, Goffin V, Edery M, et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice[J]. Endocrine reviews, 1998, 19(3): 225-268.
[3] Rubert J, Qian Z, Andraos R, et al.  Bim and Mcl-1 exert key roles in regulating JAK2 V617F cell survival[J]. BMC cancer, 2011, 11(1): 1.

Chemical Properties

StorageStore at -20°C
M.Wt563.47
Cas No.1092499-93-8 (free base)
FormulaC27H28F2N6O.2HCl
Solubility≥214 mg/mL in DMSO, ≥8.03 mg/mL in EtOH with ultrasonic and warming, <2.53 mg/mL in H2O
Chemical Name4-[[2,6-difluoro-4-[3-(1-piperidin-4-ylpyrazol-4-yl)quinoxalin-5-yl]phenyl]methyl]morpholine;dihydrochloride
SDFDownload SDF
Canonical SMILESC1CNCCC1N2C=C(C=N2)C3=NC4=C(C=CC=C4N=C3)C5=CC(=C(C(=C5)F)CN6CCOCC6)F.Cl.Cl
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

JAK2V617F突变SET-2细胞

溶解方法

该化合物在DMSO中的溶解度大于214mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

1 μmol/L,24和48 h

应用

NVP-BSK805阻断JAK2V617F细胞的生长,并诱导细胞凋亡,GI50<100 nmol/L。NVP-BSK805以剂量和时间依赖的方式诱导JAK2V617F突变体SET-2细胞的凋亡。在JAK2V617F突变体细胞系中,NVP-BSK805有效抑制STAT5磷酸化,相较于JAK1和JAK3,NVP-BSK805显示出对JAK2的偏向性。

动物实验 [1]:

动物模型

Ba/F3 JAK2V617F-luc小鼠模型, rhEpo诱导的红细胞增多症小鼠模型

给药剂量

口服,150 mg/kg

应用

在Ba/F3 JAK2V617F细胞驱动的小鼠模型中,NVP-BSK805(150 mg/kg)抑制STAT5磷酸化、脾肿大和白血病细胞扩散。在BALB/c小鼠中,NVP-BSK805抑制rhEpo诱导的STAT5磷酸化以及rhEpo介导的红细胞增多症和脾肿大。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Baffert F, Régnier C H, De Pover A, et al. Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805[J]. Molecular cancer therapeutics, 2010, 9(7): 1945-1955.

质量控制

化学结构

NVP-BSK805 2HCl