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| 25mg |
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| 100mg |
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Purity: ≥98%
S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 effectively suppressed downstream signaling in vitro and in vivo and prevented the cellular phosphorylation of MET, AXL, and FGFRs. S49076 inhibited the growth of gastric cancer cells that were dependent on FGFR2 and MET, prevented lung carcinoma cells from migrating due to MET, and prevented hepatocarcinoma cells that expressed FGFR1/2 and AXL from forming colonies. Following oral administration of S49076, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition was established in tumor xenograft models, and this relationship correlated well with the impact on tumor growth. MET, AXL, and the FGFRs have been linked to resistance to inhibitors of VEGF/VEGFR like bevacizumab. S-49076 is presently being studied in a phase I trial for patients with advanced solid tumors.
| Targets |
FGFR1 (IC50 = 18 nM); FGFR1V561M (IC50 = 23 nM); FGFR2 (IC50 = 17 nM); FGFR2N549H (IC50 = 19 nM); FGFR3 (IC50 = 15 nM); AXL (IC50 = 7 nM); MER (IC50 = 2 nM)
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| ln Vitro |
S49076 suppresses downstream signaling and effectively prevents MET, AXL, and FGFRs from becoming phosphorylated in cells. S49076 inhibits the growth of gastric cancer cells that are dependent on FGFR2 and MET, prevents lung carcinoma cells from migrating due to MET, and prevents hepatocarcinoma cells that express FGFR1/2 and AXL from forming colonies. After incubating with 10 nM S49076 and an IC50 of 2 nM for 2 hours, there is a complete inhibition of MET phosphorylation observed. With an IC50 value of 3 nM, S49076 inhibits MET phosphorylation on this site in GTL-16 gastric carcinoma cells. S49076 inhibits AXL with an IC50 of 56 nM. With an IC50 of 33 nM, S49076 inhibits AKT-mediated AXL signaling[1].
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| ln Vivo |
It has been demonstrated that oral administration of S49076 inhibits MET and FGFR2 in tumor xenograft models in a pharmacokinetic/pharmacodynamic manner that is well correlated with its effect on tumor growth. Resistant to VEGF/VEGFR inhibitors like bevacizumab, MET, AXL, and the FGFRs have all been linked. S49076 and bevacizumab together almost completely inhibit the growth of tumors in colon carcinoma xenograft models. In tumors resistant to bevacizumab, S49076 by itself resulted in tumor growth arrest [1].
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| Cell Assay |
Cells are seeded at the proper density in 96-well microplates with media containing 10% FCS for the GTL-16 and SNU-16 viability assays. 48 hours later, serial dilutions of S49076 are added in a final volume of 150 μL per well. Following four doubling times of incubation (96 hours for GTL-16 or 120 hours for SNU-16), 15 μL of a 5 mg/mL MTT solution is added to each well, and the plates are incubated for 4 hours at 37°C. For SNU-16 and GTL-16, the formazan metabolite is dissolved in SDS and DMSO, respectively, after the MTT solution has been removed. The optical density at 540 nm is used to estimate the global viability of cells [1].
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| Animal Protocol |
Mice: The study uses female Swiss nu/nu and Balb/c mice. Mice are given the hydrochloride salt of S49076 orally in a volume of 200 μL per 20 g body weight in 1% (w/v) hydroxyethylcellulose in ammonium acetate buffer pH 4.5. For these mice, the highest dosage of S49076 that can be tolerated is 100 mg/kg/d, administered five days a week for a minimum of three weeks. 200 μL of bevacizumab per 20 g of body weight is given intraperitoneally after it has been dissolved in PBS[1].
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| References |
| Molecular Formula |
C22H22N4O4S
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| Molecular Weight |
438.4995
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| Exact Mass |
438.14
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| Elemental Analysis |
C, 60.26; H, 5.06; N, 12.78; O, 14.59; S, 7.31
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| CAS # |
1265965-22-7
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| Related CAS # |
1265965-22-7
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| Appearance |
Solid powder
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| SMILES |
C1COCCN1CC2=CNC(=C2)/C=C\3/C4=C(C=CC(=C4)CN5C(=O)CSC5=O)NC3=O
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| InChi Key |
AREYWCZYVPSHGS-NVMNQCDNSA-N
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| InChi Code |
InChI=1S/C22H22N4O4S/c27-20-13-31-22(29)26(20)12-14-1-2-19-17(8-14)18(21(28)24-19)9-16-7-15(10-23-16)11-25-3-5-30-6-4-25/h1-2,7-10,23H,3-6,11-13H2,(H,24,28)/b18-9-
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| Chemical Name |
3-[[(3Z)-3-[[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylidene]-2-oxo-1H-indol-5-yl]methyl]-1,3-thiazolidine-2,4-dione
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| Synonyms |
S-49076; S 49076; S49076
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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 |
| 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: ≥ 31 mg/mL (~70.7 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.70 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2805 mL | 11.4025 mL | 22.8050 mL | |
| 5 mM | 0.4561 mL | 2.2805 mL | 4.5610 mL | |
| 10 mM | 0.2281 mL | 1.1403 mL | 2.2805 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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