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首页 >> Signaling Pathways >> Chromatin/Epigenetics >> JAK >> Ruxolitinib (INCB018424)
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Ruxolitinib (INCB018424)JAK抑制剂

Ruxolitinib (INCB018424)

产品编号:A3012
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10mM (in 1mL DMSO) ¥700.00 现货
5mg ¥700.00 现货
25mg ¥1,500.00 现货
100mg ¥2,800.00 现货

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Sample solution is provided at 25 µL, 10mM.

引用文献

1. Hermans MAW, Schrijver B, et al. "The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release." Clin Exp Allergy. 2018 Jun 25. PMID:29939445
2. Zhang S, Li Z, et al. "Interleukin-4 Enhances the Sensitivity of Human Monocytes to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Through Upregulation of Death Receptor 4." J Interferon Cytokine Res. 2018 Apr;38(4):186-194. PMID:29638207
3. Hall BM, Balan V, et al. "p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli." Aging (Albany NY). 2017 Aug 2;9(8):1867-1884. PMID:28768895
4. Radhakrishnan H, Ilm K, et al. "MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers." Cancer Lett. 2017 Jun 23. pii: S0304-3835(17)30402-0. PMID:28649004

质量控制

化学结构

Ruxolitinib (INCB018424)

相关生物数据

INCB018424
106 BaF3 Aut (V658I), Aut (F958V) were treated for 30 min with 100 nM, 1 μM or 10 μM INCB018424 inhibitor or with DMSO as a control (-condition), lysed and subjected to Western blot analysis. Phosphorylation of JAK1 and STAT5 was detected using specific anti-pY1034/35 JAK1 and anti-pY694 STAT5. Membranes were re-probed with anti-JAK1, anti-STAT5 and anti-β-Actin antibodies as a control. Similar results were obtained in 3 independent experiments.

相关生物数据

Ruxolitinib (INCB018424)

相关生物数据

Ruxolitinib (INCB018424)

相关生物数据

Ruxolitinib (INCB018424)

相关生物数据

Ruxolitinib (INCB018424)

Ruxolitinib (INCB018424) Dilution Calculator

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化学性质

CAS号 941678-49-5 SDF Download SDF
别名 Ruxolitinib,INCB018424,INCB-018424
化学名 (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
SMILES C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
分子式 C17H18N6 分子量 306.37
溶解度 ≥15.32mg/mL in DMSO 储存条件 Store at -20°C
物理性状 A solid 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。

生物活性

描述 Ruxolitinib (INCB018424)是第一个用于临床的、有效的和选择性的JAK1/2抑制剂,IC50值为3.3 nM/2.8 nM,比对JAK3的选择性高130多倍。
靶点 JAK1 JAK2        
IC50 3.3 nM 2.8 nM        

实验操作

细胞实验[1]:

细胞系

PV患者或正常对照者体内分离的原代单核细胞

溶解方法

在DMSO中的溶解度>10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

IC50:红系祖细胞:正常捐献者 407 nM,PV捐献者 223 nM。 髓系祖细胞:正常捐献者 511 nM,PV捐献者 444 nM。时间:14天

应用

在逐渐增加浓度的INCB018424存在时,红系(BFU-E)和骨髓来源(CFU-M)克隆祖细胞的生长用集落形成实验进行评估。INCB018424剂量依赖地抑制红系和髓系祖细胞的生长,其对正常捐献者和PV患者来源的红系祖细胞的平均IC50值分别为407 nM和223 nM。而对对照和PV样品来源的髓系祖细胞(CFU-M)的IC50值分别为511 nM和444 nM。

动物实验[2]:

动物模型

C57BL/6N小鼠

剂量

75 mg/kg;口服给药

应用

小鼠在注射OVA/CpG之前或之后6 h口服给药75 mg/kg的ruxolitinib或对照,并分析CD11c 1CD81脾DCs活化标志物的表达水平。在ruxolitinib治疗小鼠中,CD40、CD80、CD86以及MHC I和II分子的表达水平均降低。小鼠在注射OVA/CpG和转入CFSE标记的OT-I细胞之前6小时或之后6小时和18小时口服给药ruxolitinib或对照,在ruxolitinib预处理小鼠中,对转入的CFSE标记OT-I细胞的分析表明,ruxolitinib减少细胞增殖、CD25的表达以及IFN的产生。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 2010, 115(15): 3109-3117.

[2] Heine A, Held S A E, Daecke S N, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood, 2013, 122(7): 1192-1202.

研究更新

1. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol. 2012 Jun;52(6):809-18. doi: 10.1177/0091270011405663. Epub 2011 May 20.
Abstract
Ruxolitinib is a JAK1/2 inhibitor that is primarily metablized by CYP3A4. A 50% reduce in ruxolitinib dosage is suggested for the combination therapy of ruxolitinib with a potent CYP3A4 inhibitor due to greatly increased PD activity of ruxolitinib; while no ruxolitinib dosage adjustment is suggested for the combination of reuxolitinib with inducers or mild/moderate inhibitors of CYP3A4 due to no significant change in PD activity.
2. Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF). J Clin Pharmacol. 2013 Jul;53(7):721-30. doi: 10.1002/jcph.102. Epub 2013 May 16.
Abstract
The PK of ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, was not significantly affected by gender and body weight indicating no need to adjust ruxolitinib dose based on these two factors.
3. Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro. Cancer Lett. 2013 Dec 1;341(2):224-30. doi: 10.1016/j.canlet.2013.08.009. Epub 2013 Aug 11.
Abstract
Ruxolitinib is a JAK inhibitor that has been approved by FDA to treat advanced myelofibrosis. Since it’s a highly selective inhibitor of JAK/STAT signaling pathway, ruxolitinib significantly reduced proliferation, colony formation and expression of pSTAT1 and pSTAT3 in HCC cells.
4. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013 Dec 12;122(25):4047-53. doi: 10.1182/blood-2013-02-485888. Epub 2013 Oct 30.
Abstract
Ruxolitinib, a JAK1/2 inhibitor, was well tolerated in MF patients participating in a randomized trial, where ruxolitinib sustainably reduced splenomegaly in patients and prolonged overall survival of patients with manageable side effects, including anemia and thrombocytopenia.
5. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol. 2013 Jul;162(2):229-39. doi: 10.1111/bjh.12375. Epub 2013 May 14.
Abstract
In the phase 3 COMFORT-II study, ruxolitinib, a JAK1/2 inhibitor, exhibited better efficacy for the treatment of MF patients than BAT in terms of HRQoL improvement, symptom relief and a few other factors.

产品描述

Ruxolitinib dihydrochloride是一种特异性的Janus相关激酶(JAK1和JAK2)小分子抑制剂,其分子式为C17H21N6O4P,分子量为404。Ruxolitinib phosphate是ATP竞争性的环戊基丙腈衍生物,抑制JAK1和JAK2。Ruxolitinib抑制JAK1/2,STAT5和ERK1 / 2的磷酸化,从而减少细胞增殖。

参考文献:
Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete cytogenetic remission in t (8; 9)(p22; p24)/PCM1-JAK2–positive chronic. 
E Lierman, D Selleslag, S Smits, J Billiet.  Blood. 20122. Ruxolitinib for the treatment of myelofibrosis. A Ostojic, R Vrhovac, S Verstovsek. Ther Clin Risk Manag. 2011