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.
|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.|
|Incubation time||30 min|
|Animal models||Tag2/transgenic mouse|
|Formulation||0.6% methylcellulose/0.5% Tween 80 solution|
|Dosages||30, 100, and 300 mg/kg/d|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 30 mg/mL|
|Source||Mol Cancer Ther (2012). Figure 2. SAR131675|
|Cell Lines||lymphatic cells|
|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|
|Source||Mol Cancer Ther (2012). Figure 1. SAR131675|
|Cell Lines||HEK cells|
|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|
Specific Inhibition of the VEGFR-3 Tyrosine Kinase by SAR131675 Reduces Peripheral and Tumor Associated Immunosuppressive Myeloid Cells.
Espagnolle N, et al. Cancers (Basel). 2014 Feb 28;6(1):472-90. PMID: 24589997.
SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities.
Alam A, et al. Mol Cancer Ther. 2012 Aug;11(8):1637-49. PMID: 22584122.
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