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RO5126766(CH5126766)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
RO5126766(CH5126766)图片
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议

产品介绍
RO5126766(CH5126766) (CH5126766) 是一流的双重 MEK/RAF 抑制剂,可通过变构抑制 BRAFV600E、CRAF、MEK 和 BRAF(IC50 分别为 8.2、56、160 nM 和 190 nM)。

Kinase assays

Inhibition of MEK1 was evaluated by a coupled assay with active MEK1 (MEK1 S218E/S222E) and unactive dephosphorylated ERK2 (MAP kinase 2/Erk 2). The phosphorylation of a fluorescent-labeled peptide substrate (FAM-Erktide, IPTTPITTTYFFFK-5FAM-COOH) by ERK2 was quantified by using the IMAP FP Screening Express Kit.

Cell lines

HCT116 cell line

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

Cells were treated with 250 nmol/L CH5126766 in 0.1% DMSO for 2 hours.

Applications

CH5126766 binding could cause MEK to adopt a conformation in which MEK could not be phosphorylated by RAF, resulting in the formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, CH5126766 did not induce MEK phosphorylation.

Animal models

HCT116 mouse xenograft model

Dosage form

CH5126766 was dissolved in distilled water containing 5% DMSO and 10% HPCD. Drugs were administrated orally once a day at 1.5 mg/kg.

Application

Daily oral administration of CH5126766 caused significant tumor regression in HCT116 mouse xenograft model.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

产品描述

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.