The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. LY3009120 is a pan RAF inhibitor with IC50 values for 15nM, 5.8nM and 9.1nM for C-Raf, B-RafV600E and BRAF-WT (measured by a whole cell-based KiNativ assay), respectively, which can be used to avoid the paradoxical activation of RAF induced by B-RafV600E selective inhibitor, like Vemurafenib and Dabrafenib. Treatment with LY3009120 at dose >41nM can dramatically decrease the level of p-ERK in the BRAF WT cell line HCT116, whereas Vemurafenib produces significant paradoxical activation with elevated p-ERK level as doses increase[1]. Potent inhibition of phosphorylation of both MEK1/2 and ERK1/2 was observed with 1 μM LY3009120 treatment in RKO and HCT 116 cell lines with high basal levels of pMEK1/2 and pERK1/2 at time point 0.5h and 2h, but not in HCT-15 and SW620 cell lines with relative low basal levels of pMEK1/2 and pERK1/2[2]. Oral administration of LY3009120 at dose of 15 or 30mg/kg b.i.d. caused a dose-dependent tumor growth inhibition in rats bearing BRAF V600E ST019VR PDX tumors[1].
作用机制
LY3009120 binds to inactive form of B-Raf (DFG-Dout).[1][3]
LY3009120 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human A375 cells
Proliferation assay
72 h
Antiproliferative activity against human A375 cells after 72 hrs by resazurin assay, IC50=9.2 nM
25965804
human A375 cells
Function assay
15 mins
Competitive binding affinity to EphA2 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.02 μM
25965804
human A375 cells
Function assay
15 mins
Competitive binding affinity to BRAF in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.031 μM
25965804
human A375 cells
Function assay
72 h
Inhibition of BRAF V600E mutant in human A375 cells assessed as inhibition of ERK phosphorylation measured after 72 hrs by ELISA assay, IC50=0.037 μM
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