1. Protein Tyrosine Kinase/RTK Apoptosis
  2. c-Met/HGFR Apoptosis
  3. Tivantinib

Tivantinib  (Synonyms: ARQ 197; (3R,4R)-ARQ 198)

目录号: HY-50686 纯度: 99.25%
COA 产品使用指南

Tivantinib 是一种高选择性 c-Met 酪氨酸激酶抑制剂,Ki 为 355 nM。

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Tivantinib Chemical Structure

Tivantinib Chemical Structure

CAS No. : 905854-02-6

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规格 价格 是否有货 数量
10 mM * 1 mL in DMSO ¥614
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5 mg ¥558
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10 mg ¥837
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50 mg ¥2800
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100 mg ¥3800
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200 mg ¥6800
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  • 生物活性

  • 实验参考方法

  • 纯度 & 产品资料

  • 参考文献

生物活性

Tivantinib is a highly selective c-Met tyrosine kinase inhibitor with a Ki of 355 nM.

IC50 & Target

Ki: 355 nM (c-Met)[1]

体外研究
(In Vitro)

Tivantinib (ARQ 197) 在无细胞和基于细胞的测定中选择性抑制 c-Met 活性。用 Tivantinib 处理的表达 c-Met 的癌细胞系表现出剂量依赖性增殖能力丧失或半胱天冬酶依赖性细胞凋亡,这与配体依赖性 c-Met 活性或组成型活性 c-Met 呈正相关。为了检查 Tivantinib 的生化抑制模式,在基于过滤垫的测定中使用重组人 c-Met 进行动力学分析。ATP的Km为50.5±2.2 μM,与ATP的Km值相近。在这些动力学研究中,Tivantinib 抑制人重组 c-Met,计算出的抑制常数 (Ki) 约为 355 nM。体外暴露于 Tivantinib 抑制 HT29 和 MKN-45 细胞中的组成型 c-Met 磷酸化,以及 HGF 诱导的 MDA-MB-231 和 NCI-H441 细胞中的 c-Met 磷酸化,IC50 为100 至 300 nM[1]
Tivantinib 是一种低分子量化合物,是同类首个口服选择性 c-Met 抑制剂[2]

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

在药理学上,Tivantinib (arq197)强烈抑制人结肠异种移植肿瘤(HT29)中c-Met的磷酸化,通过单次口服200mg /kg Tivantinib 24小时后c-Met自磷酸化的显著降低来评估。同样剂量的小鼠表明,肿瘤异种移植物暴露于持续的血浆水平的Tivantinib,与观察到的c-Met磷酸化的药理学抑制和c-Met携带癌细胞系增殖的抑制一致。测定了Cmax为5.73 μg/mL (13 μM),浓度-时间曲线下面积为12.1 μg/mL h, t1/2为2.4 h。给药10小时后,Tivantinib的血浆水平为1.3 μM,是Tivantinib对c-Met的生化抑制常数的3倍[1]

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial
分子量

369.42

Formula

C23H19N3O2

CAS 号
性状

固体

颜色

Light brown to brown

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 2 years
-20°C 1 year
溶解性数据
In Vitro: 

DMSO 中的溶解度 : 100 mg/mL (270.69 mM; 超声助溶; 吸湿的 DMSO 对产品的溶解度有显著影响,请使用新开封的 DMSO)

配制储备液
浓度 溶剂体积 质量 1 mg 5 mg 10 mg
1 mM 2.7069 mL 13.5347 mL 27.0695 mL
5 mM 0.5414 mL 2.7069 mL 5.4139 mL
查看完整储备液配制表

* 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, 2 years; -20°C, 1 year。-80°C储存时,请在2年内使用, -20°C储存时,请在1年内使用。

  • 摩尔计算器

  • 稀释计算器

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

质量
=
浓度
×
体积
×
分子量 *

Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

浓度 (start)

C1

×
体积 (start)

V1

=
浓度 (final)

C2

×
体积 (final)

V2

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

  • 方案 一

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

    Solubility: ≥ 2.5 mg/mL (6.77 mM); 澄清溶液

    此方案可获得 ≥ 2.5 mg/mL(饱和度未知)的澄清溶液。

    1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;再向上述体系中加入 50 μL Tween-80,混合均匀;然后再继续加入 450 μL 生理盐水 定容至 1 mL

    生理盐水的配制:将 0.9 g 氯化钠,溶解于 ddH₂O 并定容至 100 mL,可以得到澄清透明的生理盐水溶液。
动物溶解方案计算器
请输入动物实验的基本信息:

给药剂量

mg/kg

动物的平均体重

g

每只动物的给药体积

μL

动物数量

由于实验过程有损耗,建议您多配一只动物的量
请输入您的动物体内配方组成:
%
DMSO +
+
%
Tween-80 +
%
Saline
如果您的动物是免疫缺陷鼠或者体弱鼠,建议 DMSO 中的在最后工作液体系中的占比尽量不超过 2%。
方案所需 助溶剂 包括:DMSO ,均可在 MCE 网站选购。 Tween 80,均可在 MCE 网站选购。
计算结果
工作液所需浓度 : mg/mL
储备液配制方法 : mg 药物溶于 μL  DMSO(母液浓度为 mg/mL)。
您所需的储备液浓度超过该产品的实测溶解度,以下方案仅供参考,如有需要,请与 MCE 中国技术支持联系。
动物实验体内工作液的配制方法 : 取 μL DMSO 储备液,加入 μL  μL ,混合均匀至澄清,再加 μL Tween 80,混合均匀至澄清,再加 μL 生理盐水
连续给药周期超过半月以上,请谨慎选择该方案。
请确保第一步储备液溶解至澄清状态,从左到右依次添加助溶剂。您可采用超声加热 (超声清洗仪,建议频次 20-40 kHz),涡旋吹打等方式辅助溶解。
纯度 & 产品资料

纯度: 99.25%

参考文献
Kinase Assay
[1]

Recombinant c-Met protein (50 ng) comprising residues 974 to 1390 is incubated in a reaction buffer [50 mM Tris-HCl (pH 7.5), 2 mM DTT, 0.1 mM Na3VO4, 10 mM MgCl2, 1 mM EGTA, 0.02 mg/mL bovine serum albumin, and 10% glycerol] with various concentrations of Tivantinib or DMSO in a total volume of 20 μL. After incubating for 20 minutes at room temperature, 20 μL of 20 μM poly-Glu-Tyr substrate and 20 μL of increasing amounts of cold ATP containing 1.5 μCi of [γ-33P]ATP are added to initiate the reaction. The reaction is stopped after 5, 10, 20, 40, and 60 minutes by the addition of 10% phosphoric acid and 10 μL aliquots of the reaction mixture are spotted onto P30 filtermat in triplicate. The filters are washed thrice for 5 minutes with 0.75% phosphoric acid and once with methanol for 2 minutes. The level of radioactivity is determined by using a Wallac TriLux MicroBeta liquid scintillation counter. Nonspecific binding is determined by conducting the assay in the absence of enzyme and then subtracting the value from each of the experimental values. Reaction rates are determined in the linear range of each reaction and GraphPad Prism software is used to calculate the Km and Vmax values[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

HT29, MKN-45, MDA-MB-231, and NCI-H441 (lung cancer) human cancer cells are seeded in 96-well plates overnight in a medium with 10% FBS. Each cell line is optimized for seeding cell number to ensure a similar degree of confluence at the end of the experiment in nontreated (control) wells. The next day, cells are treated with different concentrations of Tivantinib for 24 hours at 37°C. After ARQ 197 treatment, the drug-containing medium is removed, and cells are washed twice with PBS and incubated in a drug-free medium for an additional 48 hours. Cells are then incubated and stained for 4 hours with the MTS reagent (final concentration of 0.5 mg/mL) per well and are lysed. The results are quantitated by spectrophotometry at λ=450 nm[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1][2]

Mice[1]
Female athymic nude mice are acclimated to the animal housing facility for at least 1 week before the study. Efficacy studies are done in athymic mice bearing HT29, MKN-45, or MDA-MB-231 tumor xenografts to determine the effect of ARQ 197 on tumor growth. Tumor cells [5×106 (HT29) and 8×106 (MKN-45 and MDA-MB-231) cells/animal] are inoculated s.c. on day 0. Tumor dimensions are measured by a digital caliper and tumor volumes are calculated as length×width2/2. When tumors reached a volume of ~100 mm3, mice are randomized into groups and treated daily with orally administered vehicle control or 200 mg/kg Tivantinib formulated in polyethylene glycol 400/20% Vitamin E tocopheryl polyethylene glycol succinate (60:40) at 30 mg/mL, for 5 consecutive days, followed by a 2-day dosing holiday for four cycles. Therefore, each animal received a total of 20 doses. Results are expressed as mean tumor volume±SEM. To assess differences in tumor size between groups, a Mann-Whitney nonparametric t test is performed and significance is defined as P<0.05.
Rats[2]
Six male Sprague-Dawley rats (180-220 g) are used to study the pharmacokinetics of Tivantinib. Diet is prohibited for 12 h before the experiment but water is freely available. Blood samples (0.3 mL) are collected from the tail vein into heparinized 1.5 mL polythene tubes at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after oral administration of Tivantinib (10 mg/kg). The samples are immediately centrifuged at 4000g for 8 min. The plasma obtained (100 μL) is stored at -20°C until analysis. Plasma Tivantinib concentration versus time data for each rat is analyzed by DAS (Drug and statistics) software.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献

完整储备液配制表

* 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, 2 years; -20°C, 1 year。-80°C储存时,请在2年内使用, -20°C储存时,请在1年内使用。

可选溶剂 浓度 溶剂体积 质量 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 2.7069 mL 13.5347 mL 27.0695 mL 67.6736 mL
5 mM 0.5414 mL 2.7069 mL 5.4139 mL 13.5347 mL
10 mM 0.2707 mL 1.3535 mL 2.7069 mL 6.7674 mL
15 mM 0.1805 mL 0.9023 mL 1.8046 mL 4.5116 mL
20 mM 0.1353 mL 0.6767 mL 1.3535 mL 3.3837 mL
25 mM 0.1083 mL 0.5414 mL 1.0828 mL 2.7069 mL
30 mM 0.0902 mL 0.4512 mL 0.9023 mL 2.2558 mL
40 mM 0.0677 mL 0.3384 mL 0.6767 mL 1.6918 mL
50 mM 0.0541 mL 0.2707 mL 0.5414 mL 1.3535 mL
60 mM 0.0451 mL 0.2256 mL 0.4512 mL 1.1279 mL
80 mM 0.0338 mL 0.1692 mL 0.3384 mL 0.8459 mL
100 mM 0.0271 mL 0.1353 mL 0.2707 mL 0.6767 mL
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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

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