Takeda-6d

一种RAF激酶和VEGFR2的双重抑制剂；能够抑制野生型B-RAF、突变型B-RAFV600E以及C-RAF，其IC50值分别为12nM、7nM和1.5nM，同时也能抑制VEGFR2（IC50=2.8nM）。该抑制剂对这些激酶的选择性高于其他19种激酶（IC50值均>1,000nM），但对FGFR3、PDGFRα和PDGFRβ也有抑制作用，其IC50值分别为22nM、12nM和5.5nM。此外，该化合物在表达B-RAFV600E的多种结肠癌和黑色素瘤细胞系中抑制MEK和ERK1/2的磷酸化，浓度范围为100-1,600nM。在过表达VEGFR2的KDR细胞中，该化合物抑制VEGF-A诱导的VEGFR2磷酸化，其IC50值为0.53nM。在A375黑色素瘤小鼠异种移植模型中，以10mg/kg的剂量给药时，可减少肿瘤体积。A dual inhibitor of RAF kinases and VEGFR2; inhibits wild-type B-RAF, mutant B-RAFV600E, and C-RAF (IC50s = 12, 7, and 1.5 nM, respectively), as well as VEGFR2 (IC50 = 2.8 nM); selective for these kinases over a panel of 19 additional kinases (IC50s = >1,000 nM) but does inhibit FGFR3, PDGFRα, and PDGFRβ (IC50s = 22, 12, and 5.5 nM, respectively); inhibits MEK and ERK1/2 phosphorylation in several colon cancer and melanoma cell lines expressing B-RAFV600E from 100-1,600 nM; inhibits VEGF-A-induced phosphorylation of VEGFR2 in VEGFR2-overexpressing KDR cells (IC50 = 0.53 nM); reduces tumor volume in an A375 melanoma mouse xenograft model at 10 mg/kg.分子式C27H19ClFN5O3S分子量548N#CC1(CC1)C2=C(Cl)C(C(N([H])C3=CC(OC4=NC5=C(C=C4)N=C(N([H])C(C6CC6)=O)S5)=CC=C3F)=O)=CC=C2