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Binimetinib

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Chemical Structure| 606143-89-9 同义名 : 贝美替尼 ;MEK162;ARRY-162;Brand name: Mektovi.;ARRY438162, Binimetinib;​ARRY-438162;ARRY-438162
CAS号 : 606143-89-9
货号 : A194061
分子式 : C17H15BrF2N4O3
纯度 : 99%+
分子量 : 441.227
MDL号 : MFCD22124525
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(113.32 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：

IP 2% DMSO+2% Tween80+40% PEG300+water 7 mg/mL clear

PO 0.5% CMC-Na 30 mg/mL suspension

生物活性
靶点

  • MEK

    MEK, IC50:12 nM
描述 MEKs, which are members of the MAPKK family, can activate both ERK1 and ERK2 by catalyzing the phosphorylation on T202/Y204. Also MEK itself can be phosphorylated and activated through Ras when the upstream signaling is activated by extracellular stimuli, including growth factors, hormones etc.. ARRY-162 is a potent inhibitor of MEK with IC50 value of 12 nM[1]. A cellular study showed that a panel of NSCLC cells with K-ras mutation, including Calu-1, H1792, H358, H23, H460, A549 and H157 cell lines, were relatively sensitive to ARRY-162 with IC50<5 μM, which suggested that Ras mutant may respond better to ARRY-162. Treatment with ARRY-162 induced G1 arrest at concentration of 0.5 μM and 1 μM, apoptosis and autophagy at concentration of 1 μM and 3 μM for 48 h in A549 and H157 cells with K-ras mutation, but not in H522 cells (without K-ras mutation). A further signaling study indicated that ARRY-162 can effectively inhibit MEK/ERK signaling regardless of cell sensitivity as decreased p-ERK can be observed both in the ARRY-162-sensitive and -resistant cells. For MEK inhibition may activate Akt signaling, ARRY-162 at low concentration (0.5 μM-1 μM in different cell lines) increased p-AKT and its downstream p-PRAS40 and p-GSK3 in A549, H522 and ARRY-162-resistant EKVT cells, irrespective of their sensitivity to ARRY-162. Also, the suppression of p-S6 in mTOR signaling, but not p-70S6K or p-4EBP1, is associated with the increased cell sensitivity to ARRY-162. All these suggested the inhibition of PI3K pathway may have synergy with inhibition of MEK/ERK pathway by ARRY-162 in cell growth sensitivity. As prediction, combined oral treatment with 5 mg/kg ARRY-162 and 7.5 mg/kg BMK120 suppressed the tumor growth in A549 xenografts, markedly augmented the effect on tumor growth by the agent alone.[1]
作用机制 ARRY-162 is an ATP-uncompetitive inhibitor of MEK.[1]
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.27mL

0.45mL

0.23mL

11.33mL

2.27mL

1.13mL

22.66mL

4.53mL

2.27mL
参考文献

[1]Yao W, Yue P, et al. Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. Cancer Lett. 2015 Aug 1;364(1):70-8.

[2]Serra V, Eichhorn PJ, et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest. 2013;123(6):2551-63.

[3]Patrice A. Lee, Eli Wallace, et al. Preclinical Development of ARRY-162, A Potent and Selective MEK 1/2 Inhibitor. Cancer Res 2010;70(8 Suppl):Abstract nr 2515.