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RO5126766(CH5126766)

现货
Catalog No.
B5820
Raf/MEK双重抑制剂
组合的产品项目
规格价格库存 数量
25mg
¥ 4,500.00
Ship with 10-15 days
5mg
¥ 1,400.00
Ship with 10-15 days
10mg
¥ 2,200.00
Ship with 10-15 days

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Background

RO5126766 (CH5126766) is a first-in-class dual inhibitor of Raf/MEK [1].

The RAS/RAF/MEK/ERK signaling pathway is an important signal transduction system and participates in cell differentiation, movement, division and death. Activated Ras activates RAF kinase, which then phosphorylates and activates MEK (MEK1 and MEK2) [1]. The mutations in BRAF, RAS, and NF1 are associated with many human tumors [2].

RO5126766 (CH5126766) is a first-in-class dual Raf/MEK inhibitor. In cell-free kinase assays, CH5126766 effectively inhibited the phosphorylation of MEK1 protein by RAF and the activation of ERK2 protein by MEK1 with IC50 values of 0.0082-0.056 and 0.16 μM, respectively. In NCI-H460 (KRAS Q61H) human lung large cell carcinoma cell line, RO5126766 induced cell-cycle inhibitor p27Kip1 protein expression and caused G1 arrest. In HCT116 KRAS-mutant colorectal cancer cells, RO5126766 CH5126766 completely inhibited the phosphorylation of MEK and ERK [2].

In Japanese patients with advanced solid tumors, RO5126766 exhibited the maximum tolerable dose (MTD) of 2.25 mg/day once daily [1]. In a HCT116 (G13D KRAS) mouse xenograft model, RO5126766 (1.5 mg/kg) inhibited pERK and ERK signaling and exhibited ED50 value of 0.056 mg/kg [2].

References:
[1].  Honda K, Yamamoto N, Nokihara H, et al. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 2013, 72(3): 577-584.
[2].  Ishii N, Harada N, Joseph EW, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res, 2013, 73(13): 4050-4060.

文献引用

1. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758

Chemical Properties

StorageStore at -20°C
M.Wt471.46
Cas No.946128-88-7
FormulaC21H18FN5O5S
SolubilitySoluble in DMSO
SDFDownload SDF
Canonical SMILESCC(C1=C(O2)C=C(OC3=NC=CC=N3)C=C1)=C(C2=O)CC4=C(F)C(NS(NC)(=O)=O)=NC=C4
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

酶学实验 [1]:

激酶检测

通过与活性MEK1(MEK1 S218E/S222E)和非活性脱磷酸化ERK2(MAP激酶2/Erk 2)的偶联反应测定来评估对MEK1的抑制。通过使用IMAP FP Screening Express试剂盒来定量ERK2催化的荧光标记的肽底物(FAM-Erktide,IPTTPITTTYFFFK-5FAM-COOH)的磷酸化。

细胞实验 [1]:

细胞系

HCT116细胞系

溶解方法

溶于DMSO。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

细胞用CH5126766(250 nmol/L,0.1%DMSO)处理2小时。

应用

CH5126766结合能使MEK蛋白发生构型改变导致其不能被RAF磷酸化,结果就是形成了一个稳定的MEK/RAF复合体并抑制RAF活性。跟这个机制一致的是,CH5126766并不能诱导MEK的磷酸化。

动物实验 [1]:

动物模型

HCT116小鼠异种移植模型

剂量

将CH5126766溶于含有5%DMSO和10%HPCD的蒸馏水中。药物每天口服1.5mg/kg。

应用

在HCT116小鼠异种移植模型中,每日口服CH5126766导致显著的肿瘤消退。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Ishii N, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 2013 Jul 1;73(13):4050-60.

质量控制

质量控制和MSDS

批次:

化学结构

RO5126766(CH5126766)