Tivantinib (ARQ 197) (Synonyms: ARQ-197;ARQ197) |
| رقم الكتالوجGC14256 |
Tivantinib (ARQ 197) هو مثبط انتقائي للغاية لـ c-Met tyrosine kinase مع Ki يبلغ 355 نانومتر.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 905854-02-6
Sample solution is provided at 25 µL, 10mM.
;)
_1-7.$$$37316672@70.jpg');)
;)
;)
_273-287.$$$36806353@46.jpg');)
_1-16.$$$37156877@44.jpg');)
;)
;)
;)
_1124-1138.$$$35908550@30.jpg');)
_766-780.$$$37100057@30.jpg');)
_418-432.$$$36893736@30.jpg');)
_240-255.$$$35108512@29.jpg');)
_533-545.$$$36543525@28.jpg');)
_264-276.$$$36600053@22.jpg');)
_2214998.$$$@0.jpg');)
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.
| Kinase experiment [1]: | |
|
c-Met SDS-PAGE in vitro kinase assay |
Recombinant c-Met protein (100 ng) was preincubated with increasing concentrations of Tivantinib for 30 mins at room temperature. Following preincubation, 100 μM of poly-Glu-Tyr substrate and various concentrations of ATP containing 5 μCi of [γ-32P]ATP were added to the reaction mixture. The reaction was incubated for 5 mins at room temperature and then stopped by the addition of 5 μL of SDS-polyacrylamide gel, reducing sample buffer. The samples were then loaded onto a 7.5% acrylamide gel and SDS-PAGE was performed. The phosphorylated poly-Glu-Tyr substrates were ultimately visualized by autoradiography. c-Met activity was quantified by densitometry. |
| Cell experiment [2]: | |
|
Cell lines |
EBC1, MKN45, SNU638, A549, H460 and HCC827 cells |
|
Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
|
Reaction Conditions |
0 ~ 4 nM; 72 hrs |
|
Applications |
Compared with A549, H460 and HCC827 cells, Tyr1234/Tyr1235-phosphorylated and total c-MET were highly expressed in the EBC1, MKN45 and SNU638 cells. In addition, the EGFR-addicted HCC827 cell line showed high expression of c-MET as well, which, however, was driven by EGFR signaling and thus resistant to c-MET inhibitors. |
| Animal experiment [3]: | |
|
Animal models |
Nude mice bearing 1833/TGL cell xenografts |
|
Dosage form |
30, 60 and 120 mg/kg, p.o.; q.d. |
|
Applications |
The appearance of cancer cells in the leg bones showed differences since 11 to 14 days after cell implant, and increased over time, both in control and Tivantinib-treated groups. Of note, the signal from the hindlimbs of Tivantinib-treated (30 mg/kg) mice was very similar to that of control mice as well. At the doses of 60 and 120 mg/kg, Tivantinib induced a dose-dependent delay and a reduction of bone metastatic growth. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
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. | |
| Cas No. | 905854-02-6 | SDF | |
| المرادفات | ARQ-197;ARQ197 | ||
| 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 | ||
| Canonical SMILES | O=C([C@H](C(C1=CC=C2)=CN3C1=C2CCC3)[C@@H]4C5=CNC6=CC=CC=C56)NC4=O | ||
| Formula | C23H19N3O2 | M.Wt | 369.42 |
| الذوبان | ≥ 18.471mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
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 |
| 10 mM | 0.2707 mL | 1.3535 mL | 2.7069 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 19 reference(s) in Google Scholar.)
GLPBIO products are for RESEARCH USE ONLY. Please make sure your review or question is research based.
Required fields are marked with *