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CHZ868

现货
Catalog No.
B5980
II型JAK2抑制剂
组合的产品项目
规格价格库存 数量
10mg
¥ 2,880.00
Ship with 10-15 days
25mg
¥ 4,920.00
Ship with 10-15 days

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Background

CHZ868 is a type II JAK2 inhibitor with IC50 value of 110 nM [1].

JAK2 (Janus kinase 2) is a non-receptor tyrosine kinase. Mutations in JAK2 is associated with many myeloproliferative disorders.

In CRLF2-rearranged human B-ALL cells MHH-CALL4, CHZ868 potently inhibited JAK2 phosphorylation and cell growth [1]. CHZ868 is a type II JAK2 inhibitor. In JAK2V617F SET2 cells, CHZ868 potently inhibited constitutive JAK2 and STAT5 phosphorylation, and inhibited cell proliferation with GI50 value of 59 nM. In MPLW515L mutant cells, CHZ868 potently inhibited cell proliferation and abrogated phosphorylation of Y1007/Y1008 in the JAK2 activation loop. In type I JAK inhibitor-persistent cells, CHZ868 potently and concentration-dependently inhibited JAK2 phosphorylation and proliferation of JAK2V617F or MPLW515L cells [2].

In mice with human or murine B-ALL, CHZ868 improved survival. In JAK2-dependent B-ALL mice, CHZ868 and dexamethasone synergistically induced apoptosis and improved survival compared to CHZ868 alone [1]. In Jak2V617F-driven polycythemiavera (PV), CHZ868 (30 - 40 mg/kg orally once daily) inhibited JAK-STAT signaling and significantly reduced the proportion of mutant cells in the bone marrow. In MPLW515L-induced myelofibrosis (MF), CHZ868 completely inhibited STAT3 and STAT5 phosphorylation, and reduced JAK2 phosphorylation. CHZ868 also improved survival and reduced hepatomegaly in a dose-dependent way [2].

References:
[1].  Wu SC, Li LS, Kopp N, et al. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell, 2015, 28(1): 29-41.
[2].  Meyer SC, Keller MD, Chiu S, et al. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell, 2015, 28(1): 15-28.

文献引用

1. Tvorogov D, Thomas D, et al. "Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis." Sci Adv. 2018 Nov 28;4(11):eaat3834. PMID:30498775

Chemical Properties

StorageStore at -20°C
M.Wt423.42
Cas No.N/A
FormulaC22H19F2N5O2
SolubilitySoluble in DMSO
Chemical NameN-(4-((2-((2,4-difluorophenyl)amino)-1,4-dimethyl-1H-benzo[d]imidazol-5-yl)oxy)pyridin-2-yl)acetamide
SDFDownload SDF
Canonical SMILESCN(C(NC1=CC=C(F)C=C1F)=N2)C(C2=C3C)=CC=C3OC4=CC=NC(NC(C)=O)=C4
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

CRLF2重排人B-ALL细胞MHH-CALL4,JAK2V617F SET2细胞,MPLW515L突变体细胞

溶解方法

可溶于DMSO。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

0.25-1 μM

应用

在CRLF2重排的人B-ALL细胞MHH-CALL4中,CHZ868有效抑制JAK2磷酸化和细胞生长。在JAK2V617F SET2细胞中,CHZ868(0.25-1 μM)有效抑制组成型JAK2和STAT5磷酸化,并且抑制细胞增殖,GI50为59 nM。在MPLW515L突变体细胞中,CHZ868消除JAK2激活环中Y1007/Y1008的磷酸化,抑制细胞增殖。在I型JAK抑制剂持续给予细胞中,CHZ868以剂量依赖性方式抑制JAK2V617F或MPLW515L细胞的JAK2磷酸化和增殖。

动物实验 [1]:

动物模型

Jak2V617F条件敲入小鼠

给药剂量

30-40 mg/kg,口服,每天一次

应用

CHZ868标准化脾脏和肝脏重量,表明其显著抑制髓外造血。CHZ868治疗减少了骨髓巨核细胞增生。在PMF样疾病的鼠模型中,CHZ868(40 mg/kg)显著改善了MPLW515L诱导的骨髓纤维化小鼠的存活,并以剂量依赖性方式降低肝肿大,使脾脏重量和大小正常化。CHZ868明显降低骨髓和脾网状纤维化。

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]. Meyer S C, Keller M D, Chiu S, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms[J]. Cancer cell, 2015, 28(1): 15-28.

质量控制

质量控制和MSDS

批次:

化学结构

CHZ868

相关生物数据

CHZ868