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Purity: ≥98%
Pamufetinib (TAS-115; TAS115) is a novel potent inhibitor of VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase with anticancer activity. It inhibits rVEGFR2 and rMET with IC50s of 30 and 32 nM, respectively, and has an enhanced safety profile. Tumor angiogenesis is largely dependent on VEGF receptor (VEGFR) signaling. Associated toxicities or resistance to such therapy limit the usefulness of some VEGFR signal-targeted medications, despite their approval for clinical use. In order to get around these restrictions, TAS-115 was created to impede both VEGFR2 and MET's kinase activity as well as their signal-dependent cell growth to the same extent as other known inhibitors of VEGFR or MET. TAS-115 exhibited a higher degree of kinase selectivity in comparison to sunitinib, and it resulted in a comparatively mild growth inhibition (GI50 > 10 μmol/L) in cells that were either MET or VEGFR signal-independent. Moreover, TAS-115 caused less harm than other VEGFR inhibitors in a variety of normal cells. Based on these data, TAS-115 appears to be highly specific and selective, at least when tested in vitro. Given daily for six weeks, even at a serum-saturating dose of TAS-115, TAS-115 completely suppressed the progression of MET-inactivated tumors in in vivo studies by blocking angiogenesis without causing toxicity. TAS-115's remarkable selectivity for kinases and targeted cells was linked to increased tolerability and made it possible to continue treatment without lowering the dosage or requiring a washout period. Moreover, TAS-115 significantly reduced tumor size and increased survival time in mice harboring human cancer that was amplified by MET. Based on these data, TAS-115 appears to be a novel inhibitor that targets VEGFR/MET, offering enhanced antitumor efficacy and reduced toxicity. Furthermore, it has been suggested that EGFR-mutant lung cancer may be controlled in its progression by reversing EGFR-TKI resistance and inhibiting angiogenesis through triple inhibition of EGFR, HGF/Met, and VEGF/VEGF receptor 2, which can be achieved either by a triplet of clinical drugs or by TAS-115 in combination with erlotinib.
| Targets |
VEGFR2 (IC50 = 30 nM); c-Met (IC50 = 32 nM)
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| ln Vitro |
Pamufetinib is ATP antagonistic, having inhibition constants (Ki) of 12 and 39 nM against rVEGFR2 and rMET, respectively. Similar to other known inhibitors of VEGFR or MET, pamufetinib also strongly suppresses the kinase activity of both VEGFR2 and MET, as well as their signal-dependent cell growth. In comparison to other VEGFR inhibitors, parmatetinib causes less damage to a variety of normal cells[1]. At concentrations below 10 μM, Pamufetinib has no effect on PC-9 or HCC827 cell growth; however, when combined with Erlotinib, it reverses HGF-induced resistance in the cell lines in a concentration-dependent manner. Pamufetinib inhibits the proliferation of endothelial cells and the production of VEGF by cancer cells[2].
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| ln Vivo |
Pamufetinib (50 mg/kg/d) totally stops tumor growth while the patient is receiving treatment. MET-amplified human cancer transplanted models exhibit a 48% regression from the initial tumor volume upon administration of parofendinib (200 mg/kg/d). In this model, 8 mg/kg/d is the estimated 50% effective dose (ED50) of Pamufetinib. These mice's survival is greatly extended by pamufetinib when doses of 50 or 200 mg/kg/d are given[1]. In vivo angiogenesis in PC-9/HGF tumors is inhibited by parofenib. Furthermore, even after the treatment is stopped, the doublet of erlotinib and Pamufetinib effectively inhibits the growth of PC-9/HGF tumors and delays tumor regrowth linked to prolonged inhibition of the tumor vasculature[2].
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| Enzyme Assay |
The mobility shift assay is used in studies of enzyme inhibition. In summary, a 25 μL mixture containing 1/2 the Michaelis constant (Km) level of ATP, 100 mM of HEPES (pH 7.2), 0.003% (w/v) Brij35, 0.04% (v/v) Tween 20, 10 mM of MgCl2, 1 mM of dithiothreitol, a Complete Mini EDTA-free Protease Inhibitor Cocktail Tablet, and a PhosSTOP Phosphatase Inhibitor Cocktail Tablet are combined with 1.5 μM of FL-Peptide 2 or 2 μg/mL of recombinant VEGFR2 (rVEGFR2, amino acid 790-end, N-terminal 6His Tagged) and 1.5 μM of FL-Peptide 22. The addition of 15 mM EDTA ends the 90-minute incubation period of the reaction mixture at 28°C. Using a LabChip EZ Reader, Version 2.1.82.0 (UCC Version: 1.96, CCD Version: 102), phosphorylated peptide is calculated. Utilizing a logistic regression analysis, the 50% inhibitory concentration (IC50) is determined based on the quantity of phosphorylated peptide generated in the drug-treated well and the control well. Using the ProfilerPro Kit 1-8, 192 kinase panel assays are conducted and analyzed via a mobility shift assay.
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| Cell Assay |
The MTT dye reduction method is used to measure the growth of cells. Using 10% foetal bovine serum (FBS) per well, tumor cells are seeded into 96-well plates at a density of 2×103 cells/100 mL RPMI-1640 medium. Following a 24-hour incubation period, different reagents are added to each well, and the cells are incubated for an additional 72 hours.Next, 50 μL of MTT solution (2 mg/mL) is added to each well, and the cells are incubated for a further two hours. The dark blue crystals are dissolved by adding 100 mL of dimethyl sulfoxide after the media containing the MTT solution is removed. At test and reference wavelengths of 550 and 630 nm, respectively, the absorbance of every well is measured using a microplate reader. In comparison to untreated controls, the growth percentage is displayed. Every experiment involves testing each reagent concentration at least three times, and in triplicate if possible.
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| Animal Protocol |
Each mouse has a subcutaneous SC-9 fragment inserted via a trocar into its right abdomen. Subcutaneous implants of MKN45 cell suspensions are made and inserted into each naked mouse's right abdomen. There is a calculation for the tumor volume (TV, mm3). Doses of 12.5, 50, and 200 mg/kg/d are the established TAS-115. Sunitinib's maximum tolerated dose (MTD) is 40 mg/kg/d, the dose level that has been established. In the SC-9 xenograft model, oral medication therapy is administered for either 14 or 42 days in a row. TV and body weight are measured twice a week for the duration of the therapy.
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| References |
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| Molecular Formula |
C27H23FN4O4S
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|---|---|---|
| Molecular Weight |
518.56
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| Exact Mass |
518.142
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| Elemental Analysis |
C, 62.54; H, 4.47; F, 3.66; N, 10.80; O, 12.34; S, 6.18
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| CAS # |
1190836-34-0
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| Related CAS # |
Pamufetinib mesylate;1688673-09-7
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| PubChem CID |
44247727
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| Appearance |
Solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.678
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| LogP |
4.38
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
798
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S=C(N([H])C(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])=O)N([H])C1C([H])=C([H])C(=C(C=1[H])F)OC1C([H])=C([H])N=C2C([H])=C(C(C(N([H])C([H])([H])[H])=O)=C([H])C2=1)OC([H])([H])[H]
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| InChi Key |
ORRNXRYWGDUDOG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H23FN4O4S/c1-29-26(34)19-14-18-21(15-24(19)35-2)30-11-10-22(18)36-23-9-8-17(13-20(23)28)31-27(37)32-25(33)12-16-6-4-3-5-7-16/h3-11,13-15H,12H2,1-2H3,(H,29,34)(H2,31,32,33,37)
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| Chemical Name |
4-[2-fluoro-4-[(2-phenylacetyl)carbamothioylamino]phenoxy]-7-methoxy-N-methylquinoline-6-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9284 mL | 9.6421 mL | 19.2842 mL | |
| 5 mM | 0.3857 mL | 1.9284 mL | 3.8568 mL | |
| 10 mM | 0.1928 mL | 0.9642 mL | 1.9284 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Cellular inhibition of the phosphorylation of VEGFR2, MET, and signaling factors downstream from MET by TAS-115.Mol Cancer Ther.2013 Dec;12(12):2685-96. |
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 TAS-115–induced highly potent and selective inhibition of MET and VEGFR signal-dependent cell growth.Mol Cancer Ther.2013 Dec;12(12):2685-96. |
 Kinase inhibitor-induced cell damage in normal cells.Mol Cancer Ther.2013 Dec;12(12):2685-96. |
 Chronic treatment with TAS-115 produced potent antitumor effects by inhibiting angiogenesis.Mol Cancer Ther.2013 Dec;12(12):2685-96. |
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 Antitumor efficacy of TAS-115 against MET-amplified human gastric cancer MKN45 xenograft models.Mol Cancer Ther.2013 Dec;12(12):2685-96. |
 Treatment with erlotinib plus TAS-115 inhibits angiogenesis in PC-9/HGF tumors in vivo.J Thorac Oncol.2014 Jun;9(6):775-83. |
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