Ruxolitinib(Synonyms: 芦可替尼; INCB18424)

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Ruxolitinib (Synonyms: 芦可替尼; INCB18424) 纯度: 99.83%

Ruxolitinib (INCB18424) 是有效,选择性的 JAK1/2 抑制剂, IC50 值分别为 3.3 nM 和 2.8 nM,选择性是 JAK3 的 130 多倍。Ruxolitinib 诱导自噬 (autophagy),通过毒性线粒体自噬 (mitophagy) 杀死肿瘤细胞。

Ruxolitinib(Synonyms: 芦可替尼; INCB18424)

Ruxolitinib Chemical Structure

CAS No. : 941678-49-5

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生物活性

Ruxolitinib (INCB18424) is a potent and selective JAK1/2 inhibitor with IC50s of 3.3 nM and 2.8 nM in cell-free assays, and has 130-fold selectivity for JAK1/2 over JAK3[1]. Ruxolitinib induces autophagy and kills tumor cells through toxic mitophagy[3].

IC50 & Target[1]

JAK2

2.8 nM (IC50)

JAK1

3.3 nM (IC50)

Tyk2

19 nM (IC50)

JAK3

428 nM (IC50)

体外研究
(In Vitro)

Ruxolitinib potently and selectively inhibits JAK2V617F-mediated signaling and proliferation, markedly increases apoptosis in a dose dependent manner, and at 64 nM results in a doubling of cells with depolarized mitochondria in Ba/F3 cells.
Ruxolitinib demonstrates remarkable potency against erythroid colony formation with IC50 of 67 nM, and inhibits proliferating of erythroid progenitors from normal donors and polycythemia vera patients with IC50 values of 407 nM and 223 nM, respectively[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

Ruxolitinib (180 mg/kg, orally, twice a day) results in survive rate of greater than 90% by day 22 and markedly reduces splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects in a JAK2V617F-driven mouse model[1].
In the Ruxolitinib group, the primary end point is reached in 41.9% of patients, as compared with 0.7% in the placebo group in the double-blind trial of myelofibrosis. Ruxolitinib results in maintaining of reduction in spleen volume and improvement of 50% or more in the total symptom score[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

分子量

306.37

Formula

C17H18N6

CAS 号

941678-49-5

中文名称

鲁索利替尼;卢索替尼;鲁索替尼;芦可替尼

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
溶解性数据
In Vitro: 

DMSO : ≥ 100 mg/mL (326.40 mM)

H2O : < 0.1 mg/mL (ultrasonic;warming;heat to 60°C) (insoluble)

* “≥” means soluble, but saturation unknown.

配制储备液
浓度 溶剂体积 质量 1 mg 5 mg 10 mg
1 mM 3.2640 mL 16.3201 mL 32.6403 mL
5 mM 0.6528 mL 3.2640 mL 6.5281 mL
10 mM 0.3264 mL 1.6320 mL 3.2640 mL

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效
储备液的保存方式和期限:-80°C, 6 months; -20°C, 1 month。-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液,再依次添加助溶剂:

——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用; 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶

  • 1.

    请依序添加每种溶剂: 0.5% Methylcellulose/saline water

    Solubility: 5 mg/mL (16.32 mM); Suspended solution; Need ultrasonic

  • 2.

    请依序添加每种溶剂: 5% DMAC in 0.5% methylcellulose aqueous solution

    Solubility: 5 mg/mL (16.32 mM); Suspended solution; Need ultrasonic

  • 3.

    请依序添加每种溶剂: 10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.08 mg/mL (6.79 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (6.79 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。

    将 0.9 g 氯化钠,完全溶解于 100 mL ddH₂O 中,得到澄清透明的生理盐水溶液

  • 4.

    请依序添加每种溶剂: 10% DMSO    90% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.08 mg/mL (6.79 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (6.79 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。

    将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中,再用生理盐水定容至 10 mL,完全溶解,澄清透明
  • 5.

    请依序添加每种溶剂: 10% DMSO    90% corn oil

    Solubility: ≥ 2.08 mg/mL (6.79 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (6.79 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。

  • 6.

    请依序添加每种溶剂: 10% DMSO    90% corn oil

    Solubility: ≥ 2.08 mg/mL (6.79 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (6.79 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。

*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
  • [1]. Quintas-Cardama A, 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]. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012, 366(9), 799-807.

    [3]. Tavallai M, et al. Rationally Repurposing Ruxolitinib (Jakafi (®)) as a Solid Tumor Therapeutic.Front Oncol. 2016 Jun 13;6:142.

Kinase Assay
[1]

Recombinant proteins are expressed using Sf21 cells and baculovirus vectors and purified with affinity chromatography. JAK kinase assays use a homogeneous time-resolved fluorescence assay with the peptide substrate (-EQEDEPEGDYFEWLE). Each enzyme reaction is carried out with Ruxolitinib or control, JAK enzyme, 500 nM peptide, adenosine triphosphate (ATP; 1mM), and 2% dimethyl sulfoxide (DMSO) for 1 hour. The 50% inhibitory concentration (IC50) is calculated as INCB018424 concentration required for inhibition of 50% of the fluorescent signal.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Cells are seeded at 2×103/well of white bottom 96-well plates, treated with Ruxolitinib (INCB018424) from DMSO stocks (0.2% final DMSO concentration), and incubated for 48 hours at 37°C with 5% CO2. Viability is measured by cellular ATP determination using the Cell-Titer Glo luciferase reagent or viable cell counting. Values are transformed to percent inhibition relative to vehicle control, and IC50 curves are fitted according to nonlinear regression analysis of the data using PRISM GraphPad.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Mice are fed standard rodent chow and provided with water ad libitum. Ba/F3-JAK2V617F cells (105 per mouse) are inoculated intravenously into 6- to 8-week-old female BALB/c mice. Survival is monitored daily, and moribund mice are humanely killed and considered deceased at time of death. Treatment with vehicle (5% dimethyl acetamide, 0.5% methocellulose) or Ruxolitinib (INCB018424) begin within 24 hours of cell inoculation, twice daily by oral gavage. Hematologic parameters are measured using a Bayer Advia120 analyzed, and statistical significance is determined using Dunnett testing.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献
  • [1]. Quintas-Cardama A, 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]. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012, 366(9), 799-807.

    [3]. Tavallai M, et al. Rationally Repurposing Ruxolitinib (Jakafi (®)) as a Solid Tumor Therapeutic.Front Oncol. 2016 Jun 13;6:142.

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