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LY3009120

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Chemical Structure| 1454682-72-4 同义名 : DP-4978
CAS号 : 1454682-72-4
货号 : A417155
分子式 : C23H29FN6O
纯度 : 99%+
分子量 : 424.514
MDL号 : MFCD28411374
存储条件：

粉末 Keep in dark place,Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 40 mg/mL(94.23 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 0.2 mg/mL clear

PO 0.5% CMC-Na 31 mg/mL suspension

生物活性
靶点

  • B-Raf

    BRAF(V600E), IC50:5.8 nM

    BRAF WT, IC50:15 nM

  • C-Raf/Raf-1

    C-Raf, IC50:4.3 nM
描述 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]
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
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.36mL

0.47mL

0.24mL

11.78mL

2.36mL

1.18mL

23.56mL

4.71mL

2.36mL
参考文献

[1]Henry JR, Kaufman MD, et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d] pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. J Med Chem. 2015 May 28;58(10):4165-79.

[2]Vakana E, Pratt S, et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266.

[3]Roskoski R Jr, et al. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018 Sep;135:239-258.