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Purity: ≥98%
SAR131675 (SAR-131675) is a novel, potent and selective VEGFR3 inhibitor with potential antineoplastic activity. In cell-free assays, it inhibits VEGFR3 with an IC50/Ki of 23 nM/12 nM. It is less active against Akt1, CDKs, PLK1, EGFR, IGF-1R, c-Met, Flt2, and other proteins, and is roughly 50–10 times more selective for VEGFR3 than VEGFR1/2. When primary human lymphatic cells were stimulated by the VEGFR-3 ligands VEGFC and VEGFD, SAR131675, with an IC(50) of roughly 20 nmol/L, dose-dependently inhibited their proliferation. By preventing lymphangiogenesis and TAM invasion, SAR131675—the first highly selective VEGFR-3-TK inhibitor to be reported thus far—displays notable antitumoral and antimetastatic effects in vivo.
| Targets |
VEGFR3 (IC50 = 23 nM)
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|---|---|
| ln Vitro |
SAR131675 has an IC50 of roughly 20 nM and dose-dependently suppresses the growth of primary human lymphatic cells caused by the VEGFR-3 ligands VEGFC and VEGFD. With an IC50 of 23 nM, SAR131675 dose-dependently inhibits rh-VEGFR-3-TK activity. SAR131675 has a Ki of roughly 12 nM, which inhibits VEGR-3-TK activity. With an IC50 of > 3 μM for VEGFR-1-TK activity and 235 nM for VEGFR-2-TK activity, SAR131675 inhibits these activities. SAR131675 has an IC50 of approximately 1 μM for VEGFR-1 autophosphorylation and 280 nM for VEGFR-2 autophosphorylation. SAR131675 exhibits good selectivity for VEGFR-3 while only mildly inhibiting VEGFR-2 and barely affecting VEGFR-1. At an IC50 of 239 nM, SAR131675 demonstrates a dose-dependent inhibition of VEGFA-induced VEGFR-2 phosphorylation. With IC50 values of 14 nM and 17 nM, respectively, SAR131675 significantly reduces the survival of lymphatic cells stimulated by VEGFC and VEGFD. At an IC50 of 664 nM, SAR131675 suppresses the survival induced by VEGFA. With an IC50 of roughly 30 nM, SAR131675 suppresses VEGFC-induced Erk phosphorylation in a significant and dose-dependent manner.[1]
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| ln Vivo |
SAR131675 effectively impairs embryonic vasculogenesis in zebrafish embryonic angiogenesis. At 100 mg/kg/d, SAR131675 has dramatically lowered hemoglobin content and VEGFR-3 levels by roughly 50%. FGF2-induced in vivo angiogenesis and lymphangiogenesis are effectively inhibited by SAR131675. It is possible to inhibit both VEGFR-2 and VEGFR-3 signaling with SAR131675 at a dose of 300 mg/kg. The number of angiogenic islets in the pancreas of mice treated with SAR131675 is significantly reduced by 42% when compared to the group that received vehicle treatment, and the 5-week treatment is well tolerated in the prevention study. Tumor burden is significantly reduced by 62% in the intervention study when SAR131675 is taken orally every day from week 10 to week 12.5. When SAR131675 is used as a treatment, the tumor volume is significantly reduced by 24% and 50% at 30 mg/kg/d and 100 mg/kg/d, respectively.[1]
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| Enzyme Assay |
Precoating multiwell plates with a synthetic polymer substrate called poly-Glu-Tyr (polyGT 4:1) is done. Kinase buffer (10×: 50 mM HEPES buffer, pH 7.4, 20 mM MgCl2, 0.1 mM MnCl2, and 0.2 mM Na3VO4) is used for the reaction, along with DMSO and ATP for the positive control (C+) or SAR131675 (ranging from 3-1,000 nM). VEGFR-1, VEGFR-3, and VEGFR-2 require ATP at 30 μM and 15 μM, respectively. The phosphorylated poly-GT is developed in the dark using the HRP chromogenic substrate (OPD) and probed with a phosphotyrosine-specific monoclonal antibody (mAb) conjugated to horseradish peroxidase. The addition of 100 μL 1.25 mol/L H2SO4 stops the reaction, and an Envision spectrophotometer is used to measure absorbance at 492 nm.
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| Cell Assay |
In 96-well plates coated with 0.3% gelatin, HLMVECs are seeded (5000 cells per well). In RPMI 0.1% FCS, cells are cultured with or without SAR131675 in the presence or absence of VEGFA (10 ng/mL), VEGFC (300 ng/mL), VEGFD (300 ng/mL), or FGF2 (10 ng/mL). Viable cells are measured using the Titer-glo luminescent cell viability assay five days later.
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| Animal Protocol |
Mouse: Subcutaneous injection of sterile sponge disks infused with either 200 μg of FGF2 or PBS is performed on the backs of anesthetized mice. For the first two days, the sponges receive another injection of FGF2. On the day of sponge implantation, daily oral treatment with SAR131675 (30, 100, and 300 mg/kg/d) was initiated. The animals are put to sleep seven days later, and the sponges are taken out, collected, and lysed in RIPA buffer at 4°C. Upon a 6,000 × g centrifugation, the supernatants are gathered for additional examination.
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| References |
| Molecular Formula |
C18H22N4O4
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|---|---|
| Molecular Weight |
358.39
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| Exact Mass |
358.1641052
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| CAS # |
1433953-83-3
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| Related CAS # |
(Rac)-SAR131675;1092539-44-0
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| Appearance |
Solid
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| SMILES |
CCN1C(=C(C(=O)C2=C1N=C(C=C2)C#C[C@](C)(COC)O)C(=O)NC)N
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| InChi Key |
PFMPOBVAYMTUOX-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C18H22N4O4/c1-5-22-15(19)13(17(24)20-3)14(23)12-7-6-11(21-16(12)22)8-9-18(2,25)10-26-4/h6-7,25H,5,10,19H2,1-4H3,(H,20,24)/t18-/m1/s1
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| Chemical Name |
2-amino-1-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methylbut-1-ynyl]-N-methyl-4-oxo-1,8-naphthyridine-3-carboxamide
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| Synonyms |
SAR-131675; SAR131675; SAR 131675
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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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7903 mL | 13.9513 mL | 27.9026 mL | |
| 5 mM | 0.5581 mL | 2.7903 mL | 5.5805 mL | |
| 10 mM | 0.2790 mL | 1.3951 mL | 2.7903 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.
Effect of SAR131675 on VEGFR tyrosine kinases.Mol Cancer Ther.2012 Aug;11(8):1637-49. |
Effect of SAR131675 on human primary lymphatic cells.Mol Cancer Ther.2012 Aug;11(8):1637-49. |
In vivoeffect of SAR131675 on embryonic and adult angiogenesis and lymphangiogenesis.Mol Cancer Ther.2012 Aug;11(8):1637-49. |
Effect of SAR131675 on spontaneous multistage tumor model (RIP1.Tag2; A) studies designed to target discrete stages of tumoral growth in the RIP1.Mol Cancer Ther.2012 Aug;11(8):1637-49. |
Antitumoral effect of SAR131675 treatment on a murine mammary carcinoma model.A, tumor volume monitoring in Balb/c mice in control or mice treated with SAR131675 at 30 and 100 mg/kg/d. B, murine VEGFR3 levels were quantified by ELISA in the tumor lysates of each treated group at the end of the experiment (day 21).Mol Cancer Ther.2012 Aug;11(8):1637-49. |
Antimetastatic effect of SAR131675 after 4T1 tumor resection. A, experiment schedule: SAR131675 treatment at 100 mg/kg/d started 5 days after 4T1 cell implantation in mammary fat pads;Mol Cancer Ther.2012 Aug;11(8):1637-49. |
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