SAR131675 is a VEGFR3 inhibitor with IC50/Ki of 23 nM/12 nM, about 50- and 10-fold more selective for VEGFR3 than VEGFR1/2, little activity against Akt1, CDKs, PLK1, EGFR, IGF-1R, c-Met, Flt2 etc.
SAR131675 dose dependently inhibits the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20 nM. SAR131675 dose dependently inhibits rh-VEGFR-3–TK activity with an IC50 of 23 nM. SAR131675 inhibits VEGR-3–TK activity with a Ki of about 12 nM. SAR131675 inhibits VEGFR-1–TK activity with an IC50 of > 3 μM and VEGFR-2–TK activity with an IC50 of 235 nM. SAR131675 inhibits VEGFR-1 autophosphorylation with an IC50 of about 1 μM and VEGFR-2 with an IC50 of about 280 nM. SAR131675 moderately inhibits VEGFR-2 and has very little effect on VEGFR-1, showing a good selectivity for VEGFR-3. SAR131675 inhibits VEGFA-induced VEGFR-2 phosphorylation in a dose-dependent manner, with an IC50 of 239 nM. SAR131675 potently inhibits lymphatic cell survival induced by VEGFC and VEGFD with IC50 of 14 nM and 17 nM, respectively. SAR131675 inhibits VEGFA-induced survival with an IC50 of 664 nM. SAR131675, significantly and dose dependently inhibits VEGFC-induced Erk phosphorylation, with an IC50 of about 30 nM.
In embryonic angiogenesis using the zebrafish model, SAR131675 efficiently impaires embryonic vasculogenesis. SAR131675 at 100 mg/kg/d has significantly reduced the levels of VEGFR-3 and hemoglobin content by about 50%. SAR131675 efficiently abrogates lymphangiogenesis and angiogenesis induced in vivo by FGF2. SAR131675 at a dose of 300 mg/kg is able to inhibit both VEGFR-2 and VEGFR-3 signaling. In the prevention study, 5 weeks treatment with SAR131675 is well tolerated and the number of angiogenic islets in the pancreas of SAR131675-treated mice is significantly decreased by 42%, compared with the vehicle-treated group. In the intervention study, daily oral administration of SAR131675 from week 10 to week 12.5 causes a significant decrease in tumor burden by 62%. Treatment with SAR131675 significantly reduces the tumor volume 24% and 50% at 30 mg/kg/d and 100 mg/kg/d, respectively. |
