Fruquintinib

A potent and highly selective small molecule inhibitor of VEGFR1/2/3 with IC50 of 33/3/5/0.5 nM, respectively; weakly inhibits RET, FGFR-1 and c-kit kinases; demonstrates potent inhibition on VEGF-A dependent KDR phosphorylation in HEK293-KDR cells and VEGF-A induced proliferation in primary HUVECs with IC50 of 0.6 nM and 1.7 nM, respectively; suppresses tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse; orally active.Colon Cancer Phase 3 Clinical (In Vitro) :Fruquintinib demonstrates potent inhibition on VEGF-A dependent KDR phosphorylation in HEK293-KDR cells and VEGF-A induced proliferation in primary HUVECs with IC50s of 0.6±0.2 nM and 1.7 nM, respectively. Similarly, potent VEGFR3 attenuation by fruquintinib is observed in primary HLECs, with IC50s of 1.5 nM and 4.2 nM for VEGF-C stimulated VEGFR3 phosphorylation and proliferation, respectively. Fruquintinib suppresses the tube branching, tube length and area in a concentration-dependent manner. The tubule length of primary HUVECs decreased by 74% and 94% at 0.03 and 0.3 μM of fruquintinib, respectively. Fruquintinib inhibits HUVEC tubule growth and CAM angiogenesis. Tube formation is suppressed significantly after treatment with fruquintinib at 0.3 μM for 18 hours. (In Vivo) :Gastric cancer BGC-823 model is found to be most sensitive to fruquintinib. In this model, fruquintinib inhibits tumor growth by 62.3% and 95.4~98.6%, at 0.5 and 2 mg/kg once daily dosing, respectively. When the dose is elevated to 5 mg/kg and 20 mg/kg, the tumors regress by 24.1% and 48.6%, respectively. The level of anti-tumor growth activity of fruquintinib varies in different tumor xenograft models. Fruquintinib significantly decreases the micro-vessel density even at the lowest dose of 0.8 mg/kg.