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Tivantinib (ARQ 197)

现货
Catalog No.
A8325
C-Met抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 650.00
现货
5mg
¥ 550.00
现货
20mg
¥ 1,200.00
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100mg
¥ 3,800.00
现货

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Background

Tivantinib (ARQ 197) is an oral, non–adenosine triphosphate-competitive, selective, small-molecule met proto-oncogene (c-MET) inhibitor. The calculated inhibitory constant (Ki) for tivantinib to inhibit recombinant human c-MET was approximately 355 nmol/L.

c-MET, a type of receptor tyrosine kinase, is a high-affinity receptor of the hepatocyte growth factor (HGF). Dysregulated HGF/c-MET-signaling pathway frequently occurs in human cancer [1].

Tivantinib had weak inhibitory effects on VEGF receptor-3 (Flt4), p21-activated kinase 3, calmodulin-dependent kinase II delta, and Pim-1 [1]. Tivantinib displayed cytotoxic activity against a wide panel of human tumor cell lines with an EC50 ranging from 300-600 nmol/L [4]. Remarkably, A549, H3122, PC9 (Del E746_A750), PC9 GR4 (Del E746_A750/T790M), HCC827, HCC827 GR6, H1993 and EBC-1 cell lines showed some degree of sensitivity to tivantinib, with IC50s ranging between 0.36 and 0.8 μM [5]. In tumor cell lines, GTL-16, MKN-45, Hs746T, SNU-5, EBC-1, H1993, NCI-H441, A549, HCT-116, U87-MG, A2780, and TOV-112D, tivantinib indiscriminately inhibited cell proliferation independently of c-MET gene amplification and MET protein expression with an EC50 ranging from 60 to 600 nmol/L. Further research showed that tivantinib promotes mitotic arrest, prevents cells from re-entering G1, and drives them to apoptosis, and induces programmed cell death regardless of the presence or absence of a functional MET kinase [4].

Tivantinib has demonstrated antitumor activity in a wide range of human tumor cell lines and in xenograft models of human lung, colon, prostate, pancreas, and breast cancer [1] [2] [3]. Female 4-week-old athymic nude (nu/nu) mice were used as experimental animals. Tivantinib at a dose of 120 mg/kg significantly inhibited tumor burden in the bone of treated animals compared with the controls, starting from 14 to 21 days after cell injection. Increasing doses of tivantinib decreased the number and the extent of osteolytic lesions [6].

References:
[1].  Ryohei Katayama, Aki Aoyama, Takao Yamori, et al. Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition. Cancer Research, 2013, 73(10): 3087-3097.
[2].  Andrew J.Wagner, John M. Goldberg, Steven G. DuBois, et al. Tivantinib (ARQ 197), a Selective Inhibitor of MET, in Patients with Microphthalmia Transcription Factor–Associated Tumors. Cancer, 2012: 5894-5902.
[3].  N. Yamamoto, H. Murakami, T. Nishina, et al. The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors. Annals of Oncology, 2013, 00: 1–7.
[4].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clin Cancer Res, 2013, 19(9):2381-92.
[5].  Cristina Basilico, Selma Pennacchietti, Elisa Vigna, et al. Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET. Clinical Cancer Research, 2013, 19(9): 2381–92.
[6].  Sara Previdi, Giovanni Abbadessa, Francesca Dalò, et al. Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther, 2011, 11(1):214-23.

文献引用

1. Cheriyan VT, Alsaab H, et al. "A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers." Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID:30038713
2. Shi P, Oh YT, et al. "Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment." Cancer Lett. 2016 Jul 19;380(2):494-504. PMID:27450722

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt369.42
Cas No.905854-02-6
FormulaC23H19N3O2
SynonymsARQ-197;ARQ197
Solubility≥18.471mg/mL in DMSO
Chemical Name(3S,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione
SDFDownload SDF
Canonical SMILESO=C([C@H](C(C1=CC=C2)=CN3C1=C2CCC3)[C@@H]4C5=CNC6=CC=CC=C56)NC4=O
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

激酶实验 [1]:

体外c-Met SDS-PAGE激酶试验

将100 ng重组c-Met蛋白与浓度递增的ARQ-197置于室温下预温育30分钟。随后,将100 μM聚Glu-Tyr底物和不同浓度的ATP(含5 μCi [γ-32P]ATP)加到反应混合物中。反应于室温下进行5分钟,然后加入5 μL SDS聚丙烯酰胺凝胶,减少样本缓冲液,终止反应。将样品加到7.5%丙烯酰胺胶上,进行SDS-PAGE。通过放射自显影观察磷酸化的聚Glu-Tyr底物。通过光密度法测定c-Met活性。

细胞实验 [2]:

细胞系

EBC1、MKN45、SNU638、A549、H460和HCC827细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

0 ~ 4 nM;72小时

实验结果

与A549、H460和HCC827细胞相比,Tyr1234/Tyr1235-磷酸化c-MET和总c-MET在EBC1、MKN45和SNU638细胞中高表达。此外,嗜EGFR的HCC827细胞也高表达c-MET,但受EGFR信号传导驱动,因此对c-MET抑制剂具有抗性。

动物实验 [3]:

动物模型

携带1833/TGL细胞异种移植物的裸小鼠

给药剂量

30、60和120 mg/kg,口服给药,每日1次

实验结果

在细胞植入后的第11 ~ 14天开始,腿骨癌细胞在对照和Tivantinib处理组中显示差异,并随时间增加。而且,Tivantinib治疗小鼠 (30 mg/kg) 的后肢信号与对照组相似。在60和120 mg/kg剂量下,Tivantinib呈剂量依赖性地诱导骨癌转移生长的延迟和减少。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Munshi N, Jeay S, Li Y, Chen CR, France DS, Ashwell MA, Hill J, Moussa MM, Leggett DS, Li CJ. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010 Jun;9(6):1544-53.

[2]. Ryohei Katayama, Aki Aoyama, Takao Yamori, et al. Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition. Cancer Research, 2013, 73(10): 3087-3097.

[3]. Sara Previdi, Giovanni Abbadessa, Francesca Dalò, et al. Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther, 2011, 11(1):214-23.

生物活性

描述 Tivantinib (ARQ 197)是第一个非ATP竞争性的c-Met抑制剂,Ki值为0.355 μM,对Ron几乎没有作用,对EGFR、InsR、PDGFRα和FGFR1/4没有抑制作用。
靶点 c-Met          
IC50 0.355 μM (Ki)          

质量控制

化学结构

Tivantinib(ARQ 197)

相关生物数据

Tivantinib(ARQ 197)

相关生物数据

Tivantinib(ARQ 197)

相关生物数据

Tivantinib(ARQ 197)

相关生物数据

Tivantinib(ARQ 197)