Tivantinib (ARQ 197)
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
Tivantinib（ARQ 197）是一种可口服的、非ATP竞争性的和选择性的met原癌基因 （c-MET）小分子抑制剂，抑制重组人c-MET，Ki值约为355 nmol/L。
c-MET，一种受体酪氨酸激酶，是肝细胞生长因子（HGF）的高亲和性受体。HGF/c-MET信号通路的失调在人类癌症中频繁发生[1]。
Tivantinib对VEGF受体-3（FLT4）、p21激活激酶3、钙调蛋白依赖性蛋白激酶II delta和Pim-1具有弱的抑制活性[1]。Tivantinib对广泛的人类肿瘤细胞系具有细胞毒性效应，EC50值介于300-600 nmol / L[4]。值得注意的是，A549、H3122、PC9 (Del E746_A750)、PC9 GR4 (Del E746_A750/T790M)、HCC827、HCC827 GR6、H1993和EBC-1细胞系对tivantinib具有一定程度的敏感性，IC50值介于0.36-0.8 μM之间[5]。在肿瘤细胞系GTL-16、MKN-45、Hs746T、SNU-5、EBC-1、H1993、NCI-H441、A549、HCT-116、U87-MG、A2780和TOV-112D中，tivantinib以不依赖c-MET基因扩增和MET蛋白表达的方式抑制细胞增殖，EC50值介于60-600 nmol/L。进一步研究表明，tivantinib促进有丝分裂停滞，阻止细胞重新进入G1期，驱动细胞凋亡，诱导程序性细胞死亡，无论功能MET激酶是否存在[4]。
Tivantinib在广泛的人类肿瘤细胞系和人肺癌、结肠癌、前列腺癌、胰腺癌和乳腺癌异种移植模型中均具有抗肿瘤活性[1][2][3]。在4周龄的雌性无胸腺（nu/nu）裸鼠中，tivantinib以120 mg/kg的剂量在细胞注射后的14到21天给药，与对照相比，tivantinib显著抑制骨中肿瘤负担。增加tivantinib的剂量可减少溶骨性病变的数量和程度[6]。
参考文献：
[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.
- 1. MINHUI LI, TINGTING JIANG, et al. "Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells." Exp Ther Med. 2020 Sep;20(3):2765-2773. PMID: 32765771
- 2. 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
- 3. 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
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 369.42 |
| Cas No. | 905854-02-6 |
| Formula | C23H19N3O2 |
| Synonyms | ARQ-197;ARQ197 |
| Solubility | ≥18.47 mg/mL in DMSO; ≥2.29 mg/mL in H2O with gentle warming; ≥4.32 mg/mL in EtOH |
| 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 |
| SDF | Download SDF |
| Canonical SMILES | O=C([C@H](C(C1=CC=C2)=CN3C1=C2CCC3)[C@@H]4C5=CNC6=CC=CC=C56)NC4=O |
| 运输条件 | 蓝冰运输或根据您的需求运输。 |
| 一般建议 | 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。溶液形式一般不宜长期储存，请尽快用完。 |
| 激酶实验 [1]: | |
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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]: | |
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动物模型 |
携带1833/TGL细胞异种移植物的裸小鼠 |
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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。 |
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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. |
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| 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) | |||||
质量控制和MSDS
- 批次：
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