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Purity: ≥98%
Pamufetinib (TAS-115) mesylate, the mesylate salt of Pamufetinib (TAS115; TAS 115), is an inhibitor of VEGFR and c-MET 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 produced relatively weak growth inhibition (GI50 > 10 μmol/L) in cells that were either MET or VEGFR signal-independent, and its kinase selectivity was more specific than sunitinib's. Moreover, TAS-115 caused less harm to different types of normal cells than other VEGFR inhibitors. According to these findings, TAS-115 is remarkably specific and selective, at least when used in vitro. Even at a serum-saturating dose of TAS-115, daily administration for six weeks completely suppressed the growth of MET-inactivated tumors by blocking angiogenesis without causing toxicity in in vivo studies. Improved tolerability and the capacity to continue treatment without dosage reduction or a washout period were linked to TAS-115's notable selectivity for kinases and targeted cells. Additionally, in MET-amplified human cancer-bearing mice, TAS-115 produced a significant reduction in tumor size and extended survival. Based on these data, TAS-115 appears to be a novel inhibitor that targets VEGFR/MET, better able to suppress tumor growth while posing less side effects. The triple inhibition of EGFR, HGF/Met, and VEGF/VEGF receptor 2 by either a triplet of clinical drugs or TAS-115 in combination with erlotinib has also been reported to be helpful in reversing EGFR-TKI resistance and preventing angiogenesis, which may help control the progression of EGFR-mutant lung cancer. These findings are noteworthy.
| Targets |
VEGFR2 (IC50 = 30 nM); c-Met (IC50 = 32 nM)
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| ln Vitro |
Pamufetinib mesylate significantly inhibits the proliferation of MET-amplified cancer cells (GI50=0.032-0.362 μM) and strongly suppresses the VEGF-dependent proliferation of HUVECs (IC50=0.019 μM) as a MET-targeted inhibitor. In comparison to other VEGFR-targeted kinase inhibitors, pamufetinib mesylate is significantly less toxic in a variety of normal cell lines[1]. In PC-9 and HCC827 cells, erlotinib resistance, Met phosphorylation, and VEGF production induced by HGF are all inhibited by crizotinib and Pamufetinib mesylate[2].
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| ln Vivo |
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| Enzyme Assay |
Mobilization shift assays were used in studies of enzyme inhibition. Briefly, 0.3 μg/mL of recombinant MET (rMET, N-terminal glutathione S-transferase (GST) Tag; Carna Biosciences) and 1.5 μmol/L of FL-Peptide 2 (Caliper Life Sciences) or 2 μg/mL of recombinant VEGFR2 (rVEGFR2, amino acid 790-end, N-terminal 6His Tagged; Upstate) and 1.5 μmol/L of FL-Peptide 22 (Caliper Life Sciences) were added to a 25 μL mixture containing 1/2 the Michaelis constant (Km) level of ATP, 100 mmol/L of HEPES (pH 7.2), 0.003% (w/v) Brij35, 0.04% (v/v) Tween 20, 10 mmol/L of MgCl2, 1 mmol/L of dithiothreitol, a Complete Mini EDTA-free Protease Inhibitor Cocktail Tablet (Roche Diagnostics, K.K.), and a PhosSTOP Phosphatase Inhibitor Cocktail Tablet (Roche Diagnostics, K.K.), with the addition of 0.05% (w/v) CHAPSO only in the case of rVEGFR2. The reaction mixture was stopped by adding 15 mmol/L of EDTA after it had been incubated for 90 minutes at 28°C. Utilizing a LabChip EZ Reader, Version 2.1.82.0 (UCC Version: 1.96, CCD Version: 102), the phosphorylated peptide was computed. Utilizing a logistic regression analysis, the 50% inhibitory concentration (IC50) was determined based on the quantity of phosphorylated peptide generated in the drug-treated well and the control well. The ProfilerPro Kit 1-8 (Caliper Life Sciences) was used to conduct 192 kinase panel assays, which were then analyzed using a mobility shift assay.
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| Cell Assay |
For 72 hours, MRC-5 (1000 cells/300 μL) and tumor cells (8000 cells/800 mL) in the upper chamber of Transwell collagen-coated chambers are cocultured with or without TAS-115 (1.0 μM) or erlotinib (0.3 μM). Next comes the removal of the upper chamber. Utilizing the MTT assay, cell viability is determined[2].
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| References |
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| Molecular Formula |
C28H27FN4O7S2
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| Molecular Weight |
614.664987802505
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| Exact Mass |
614.13051972
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| Elemental Analysis |
C, 54.71; H, 4.43; F, 3.09; N, 9.12; O, 18.22; S, 10.43
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| CAS # |
1688673-09-7
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| Related CAS # |
Pamufetinib;1190836-34-0
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| Appearance |
Solid powder
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| SMILES |
CNC(=O)C1=CC2=C(C=CN=C2C=C1OC)OC3=C(C=C(C=C3)NC(=S)NC(=O)CC4=CC=CC=C4)F.CS(=O)(=O)O
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| InChi Key |
NUYQWFCUOAVQAL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H23FN4O4S.CH4O3S/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;1-5(2,3)4/h3-11,13-15H,12H2,1-2H3,(H,29,34)(H2,31,32,33,37);1H3,(H,2,3,4)
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| Chemical Name |
4-[2-fluoro-4-[(2-phenylacetyl)carbamothioylamino]phenoxy]-7-methoxy-N-methylquinoline-6-carboxamide;methanesulfonic acid
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| Synonyms |
TAS115 mesylate; TAS115; Pamufetinib; TAS-115; TAS 115; Pamufetinib mesylate
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO : ~75 mg/mL (~122.02 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6269 mL | 8.1344 mL | 16.2689 mL | |
| 5 mM | 0.3254 mL | 1.6269 mL | 3.2538 mL | |
| 10 mM | 0.1627 mL | 0.8134 mL | 1.6269 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.
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