SAR131675 is a selective inhibitor of VEGFR-3 with IC50 value of 20nM [1].
SAR131675 is an ATP-competitive inhibitor. It inhibits recombinant human VEGFR-3 with IC50 value of 23nM and inhibits the kinase activity of VEGFR-3 with Ki value of 12nM. SAR131675 is found to be cell permeable and inhibits VEGFR-3 autophosphorylation in HEK cells with IC50 values ranging from 30nM to 50nM. SAR131675 shows IC50 values of >3μM and 235nM against VEGFR-1 and VEGFR-2, respectively. It also havs no inhibitory effect on a panel of 65 kinases, 107 nonkinase enzymes and receptors and on 21 ion channels. Moreover, SAR131675 inhibits lymphatic cell survival induced by VEGFC and VEGFD with IC50 values of 14nM and 17nM. On another hand, SAR131675 exerts inhibition of the migration induced by VEGFA or VEGFC with IC50 values of 100nM and <30nM in HLMVEC cells, respectively [1].
In vivo, SAR131675 abrogates lymphangiogenesis and angiogenesis induced by FGF2. It also shows antitumor activity in the mice models. Treatment with SAR131675 significantly reduces the tumor volume of 4T1 mammary carcinoma tumors [1]
Despite the promising findings, SAR131675 development was terminated during preclinical development due to adverse metabolic effects[2].
References:
[1] Alam A, Blanc I, Gueguen-Dorbes G, et al. SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities. Molecular cancer therapeutics, 2012, 11(8): 1637-1649.
[2] Paillasse MR, Esquerré M, Bertrand FA, et al. Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy. Cancer Res Commun. 2022;2(11):1504-1519.
