生物活性

• 靶点

  c-Kit IC50:0.01µM

  Aurora Kinase B IC50:0.047µM

  PDGFRβ IC50:0.1µM

  Aurora Kinase A IC50:0.85µM

  TBK1 IC50:1.4µM

  更多

• 描述Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. SU6668 is a novel inhibitor of these receptors. SU6668 is a competitive inhibitor, with regard to ATP, of Flk-1 trans-phosphorylation (K_i = 2.1 μM), FGFR1 trans-phosphorylation (K_i = 1.2 μM), and PDGFR autophosphorylation (K_i = 0.008 μM). HUVECs stimulated by VEGF exhibit an increase in tyrosine phosphorylation of KDR. Treatment of cells with SU6668 inhibited this increase in a dose-dependent manner. SU6668 also inhibited PDGF-stimulated PDGFRβ tyrosine phosphorylation in NIH-3T3 cells overexpressing PDGFRβ at a minimum concentration of 0.03–0.1 μM. SU6668 inhibited acidic FGF-induced phosphorylation of the FGFR1 substrate 2 (FRS-2) at concentrations of 10 μM and higher. SU6668 inhibited VEGF-driven mitogenesis of HUVECs in a dose-dependent manner with a mean IC₅₀ of 0.34 ± 0.05 μM. p.o. administered SU6668 induced dose-dependent inhibition of A431 tumor growth in the s.c. xenograft model in athymic mice. SU6668 was also efficacious when administered i.p. or p.o. in additional xenograft models, including A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 cells. These in vivo data demonstrated that SU6668 readily induced >75% growth inhibition against a broad range of tumor types^[3].
• 作用机制In both FGFR1 and PDGFR, the oxindole core structure of SU6668 forms hydrogen bonds with the receptor backbone at the hinge region^[3].