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Avutometinib
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。
Avutometinib图片
CAS NO:946128-88-7
包装与价格:
包装价格(元)
10 mM * 1 mL in DMSO电议
5mg电议
10mg电议
50mg电议
100mg电议
200mg电议
500mg电议

产品名称
Ro 5126766
CH5126766
产品介绍
Avutometinib (Ro 5126766) 是一种有效的双重MEK/RAF抑制剂,抑制BRAFV600ECRAF,MEK,和BRAFIC50分别为 8.2 nM, 56 nM, 160 nM 和 190 nM。
生物活性

Avutometinib (Ro 5126766) is a first-in-class dualMEK/RAFinhibitor that allosterically inhibitsBRAFV600E,CRAF,MEK, andBRAF(IC50: 8.2, 56, 160 nM, and 190 nM, respectively).

IC50& Target[1]

MEK

160 nM (IC50)

BRafV600E

8.2 nM (IC50)

Braf

190 nM (IC50)

CRAF

56 nM (IC50)

体外研究
(In Vitro)

Avutometinib (Ro 5126766) is an allosteric inhibitor that binds directly to MEK and prevents its phosphorylation by RAF through the formation of a stable RAF-MEK complex. Ro 5126766 inhibits both the phosphorylation of MEK by RAF and the activation of ERK by MEK. In cell-free MEK and RAF kinase assays, Avutometinib effectively inhibits activation of ERK2 by MEK1 with an IC50of 160 nM (SD=±0.043) and inhibits the phosphorylation of MEK1 protein byBRAF(IC50=190 nM, SD=±0.003),BRAFV600E(IC50=8.2 nM, SD=±0.0015), andCRAF(IC50=56 nM, SD=±0.016). Avutometinib effectively inhibits both MEK and ERK phosphorylation in a panel of human tumor cell lines includingKRAS/HRASandBRAFmutant cell lines andKRAS/HRASandBRAFwild-type cells[1]. In order to investigate whether the mevalonate pathway affects the sensitivity to MEK inhibitors, human breast cancer MDA-MB-231 cells harboringKRASandBRAFmutations are treated Avutometinib, with or without statins, which inhibits HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. The combined treatment of Avutometinib with XU 62-320 demonstrates more significant reduction in cell growth in a dose-dependent manner than the single treatment of Avutometinib. The marked combined effects of Avutometinib at 40 nM and XU 62-320 at 0.3 μM is also confirmed on the suppression of the colony formation of the cells[2].

体内研究
(In Vivo)

InKRAS-mutant xenograft models, Avutometinib (Ro 5126766) inhibits growth and causes tumor regressions more effectively than another allosteric MEK inhibitor, PD0325901. Preclinical data from a series of human tumor mouse xenograft models indicates an ED50for Ro 5126766 of 0.03 to 0.23 mg/kg and an ED90of 0.15 to 1.56 mg/kg. These effective doses are associated with target trough concentrations of 17 to 133 ng/L and 87 to 901 ng/mL, respectively.[1]. In this experiment, Avutometinib or PD0325901 is administrated at their maximum tolerated dose (MTD) in the HCT116 model (1.5 and 25 mg/kg, respectively). These doses inhibit pERK and ERK signaling output at similar degrees in the tumors from the drug-treated mice at 4 hours from the first drug administration. Moreover, in HCT116 models, the ED50for Avutometinib and PD0325901 are 0.056 and 0.80 mg/kg, respectively. Therefore, the doses used for this experiment are 26.8- and 31.3-fold higher doses than the 50% effective doses, respectively. Daily oral administration of either drug causes significant tumor regression of each these tumors. However, whereas inhibition of tumor growth is maintained for the entire 28-day treatment period in Avutometinib-treated mice, tumor models receiving PD0325901 become refractory after 10 days of treatment[3].

Clinical Trial
分子量

471.46

性状

Solid

Formula

C21H18FN5O5S

CAS 号

946128-88-7

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder-20°C3 years
4°C2 years
In solvent-80°C6 months
-20°C1 month
溶解性数据
In Vitro: 

DMSO : 125 mg/mL(265.13 mM;Need ultrasonic)

配制储备液
浓度溶剂体积质量1 mg5 mg10 mg
1 mM2.1211 mL10.6054 mL21.2107 mL
5 mM0.4242 mL2.1211 mL4.2421 mL
10 mM0.2121 mL1.0605 mL2.1211 mL
*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效
储备液的保存方式和期限:-80℃, 6 months; -20℃, 1 month。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液,再依次添加助溶剂:

——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用; 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶

  • 1.

    请依序添加每种溶剂: 10% DMSO    40%PEG300   5%Tween-80   45% saline

    Solubility: ≥ 2.08 mg/mL (4.41 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.41 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。

    将 0.9 g 氯化钠,完全溶解于 100 mL ddH2O 中,得到澄清透明的生理盐水溶液
  • 2.

    请依序添加每种溶剂: 10% DMSO    90% (20%SBE-β-CDin saline)

    Solubility: ≥ 2.08 mg/mL (4.41 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.41 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。

    将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中,再用生理盐水定容至 10 mL,完全溶解,澄清透明
  • 3.

    请依序添加每种溶剂: 10% DMSO    90%corn oil

    Solubility: ≥ 2.08 mg/mL (4.41 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.41 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。

*以上所有助溶剂都可在本网站选购。