| TSU-68 is an ATP-competitive and highly potent PDGFR inhibitor. TSU-68 potently inhibits PDGFRβ, VEGFR2, and FGFR1 with IC50s of 0.06, 2.43, and 3.04 µM, respectively. In addition, the IC50 of TSU-68 against EGF-R is ??00 µM.[1] TSU-68 displays potent inhibitory activities against Flk-1 trans-phosphorylation, FGFR1 trans-phosphorylation, and PDGFR autophosphorylation with Ki values of 2.1 µM, 1.2 µM, and 8 nM, respectively. Moreover, the IC50s of TSU-68 against insulin-like growth factor I receptor (IGF-IR), Met, Src, Lck, Zap70, Abl, and cyclin-dependent kinase 2 (CDK2) are at least 10 µM. In vitro, TSU-68 treatment does dependently inhibits the increase of tyrosine phosphorylation of KDR stimulated by VEGF in HUVECs. TSU-68 (30-100 nM) also inhibits PDGF-stimulated PDGFRβ tyrosine phosphorylation in NIH-3T3 cells overexpressing PDGFRβ. In vivo in athymic mice, administration of TSU-68 (oral or i.p.) significantly inhibits the growth of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. In addition, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model, treatment with TSU-68 (75 mg/kg/day) significantly suppresses tumor angiogenesis and vascularization throughout the entire 22-day observation period.[2] In a s.c. tumor model of HT29 human colon carcinoma in athymic mice, TSU-68 (200 mg/kg) greatly inhibits tumor growth, with 60% inhibition at 14 days of treatment.[3] In vivo, TSU-68 also modulates the premetastatic niche through suppression of the inflammatory response, and thus inhibits liver metastasis of colon cancer xenografts.[4] |
