SAR131675 is the first highly specific VEGFR-3-TK inhibitor, which displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion. SAR131675 inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC50 values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20 nmol/L. SAR131675 showed a potent antitumoral effect in several orthotopic and syngenic models, including mammary 4T1 carcinoma and RIP1.Tag2 tumors. Interestingly, SAR131675 significantly reduced lymph node invasion and lung metastasis, showing its antilymphangiogenic activity in vivo. SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors.
J Sport Health Sci. 2022 Jul;11(4):466-478.
Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
SAR131675 purchased from AbMole
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Source | Mol Cancer Ther (2012). Figure 2. SAR131675 |
| Method | migration assay | |
| Cell Lines | lymphatic cells | |
| Concentrations | 30–300 nmol/L | |
| Incubation Time | 5 d | |
| Results | SAR131675 potently inhibited VEGFCinduced migration with an IC50 < 30 nmol/L (Fig. 2B) and VEGFA-induced migration with an IC50 of about 100 nmol/L |
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Source | Mol Cancer Ther (2012). Figure 1. SAR131675 |
| Method | migration assays | |
| Cell Lines | HEK cells | |
| Concentrations | 100 mmol/L | |
| Incubation Time | 1 h | |
| Results | SAR131675 was seen to be cell permeable and inhibited VEGFR-3 autophosphorylation in a dose dependent manner with an IC50 ranging from 30 to 50 nmol/L |
| Cell Experiment | |
|---|---|
| Cell lines | HEK cell |
| Preparation method | Experiments were conducted as described previously (35). Twenty-four hours after transfection, the cells were treated during 1 hour with orthovanadate (100 mmol/L), harvested, collected, and, after counting, distributed in 5-mL tubes in the presence of the indicated concentration of SAR131675. |
| Concentrations | 3–1,000 nmol/L |
| Incubation time | 30 min |
| Animal Experiment | |
|---|---|
| Animal models | Tag2/transgenic mouse |
| Formulation | 0.6% methylcellulose/0.5% Tween 80 solution |
| Dosages | 30, 100, and 300 mg/kg/d |
| Administration | oral |
| Molecular Weight | 358.39 |
| Formula | C18H22N4O4 |
| CAS Number | 1433953-83-3 |
| Solubility (25°C) | DMSO ≥ 25 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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