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]
Binimetinib 动物研究
Dose
Mice: min = 6 mg/kg[2] (p.o.), max = 30 mg/kg[4] (p.o.)
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