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Avutometinib

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Chemical Structure| 946128-88-7 同义名 : CH5126766;Ro 5126766
CAS号 : 946128-88-7
货号 : A245684
分子式 : C21H18FN5O5S
纯度 : 98%
分子量 : 471.462
MDL号 : MFCD27987901
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 120 mg/mL(254.53 mM)，配合低频超声助溶，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：
生物活性
靶点

  • B-Raf

    BRAF V600E, IC50:8.2 nM

    BRAF, IC50:19 nM

  • C-Raf/Raf-1

    CRAF, IC50:56 nM
描述 The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Among them, B-RAF is the most frequently mutated protein kinase in human cancers. Ro 5126766 is a unique and allosteric MEK/RAF signaling inhibitor with IC50 values of 8.2, 19, 56 and 160nM for BRAFV600E mutant, BRAF, CRAF and MEK1 (measured by cell-free kinase assays), respectively. Treatment with Ro 5126766 at dose ranging in 0.01-10μM for 2h can reduce levels of both p-MEK and p-ERK dose-dependently till to undetectable levels in HCT116 KRAS-mutant colorectal cancer cells, whereas other MEK inhibitors PD0325901/GSK1120212 only inhibited ERK phosphorylation and either GDC-0879 or PLX-4720, the RAF inhibitor, induced p-MEK and p-ERK in response to paradoxical activation of RAF kinase as previous report. Consistent with the in vitro study, Ro 5126766 showed more effective inhibition on ERK signaling output than PD0325901 in chronically treated tumors with RAS mutations in the Calu-6 (NSCLC, KRAS Q61K) xenograft models. Oral administration of Ro 5126766 at dose of 1.5mg/kg, every day for 11 days showed more anti-tumor effect than PD0325901. Also Ro 5126766 at dose of 2mg/kg can cease the tumor growth on the PD0325901-refractory tumors in the HCT116 xenograft tumor model. Both of these more prolonged growth inhibition with Ro 5126766 was accompanied with suppression on both ERK signaling, p-MEK and p-ERK[1].
作用机制 The binding of Ro 5126766 caused MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF, thus resulting in formation of a stable MEK/RAF complex and inhibition of RAF kinase.[1]
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
HCT116 cell Function assay 96 h Inhibition of human HCT116 cell growth after 96 hrs by counting kit-8 analysis, IC50=0.04 μM 24900832
human A549 cells 10 μM Function assay 1 h Inhibition of MEK1 in human A549 cells assessed as reduction in pErk1/2 level at 10 uM after 1 hr by Western blotting analysis 25766633
human C32 cells Growth inhibition assay Growth inhibition of human C32 cells harboring R-Raf V600E mutant, IC50=0.047 μM 24900832
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.12mL

0.42mL

0.21mL

10.61mL

2.12mL

1.06mL

21.21mL

4.24mL

2.12mL
参考文献

[1]Souers AJ, Leverson JD, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.