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/比美替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SNU-1235
1 μM
48 hours
To assess the inhibition of MAPK and JAK/STAT pathways, cell viability, apoptosis, and the expression of antigen presenting machinery. Results showed that combination treatment led to inhibition of MAPK and JAK/STAT pathways, downregulation of PD-L1 expression, and significant reduction in cell viability.
Cancer Immunol Immunother. 2025 Mar 19;74(5):154
Neonatal rat cardiomyocytes (NRCM)
10 µM
1 h
Binimetinib inhibited ERK1/2 activation, prevented cardiomyocyte hypertrophy but also increased cell death.
Nat Commun. 2020 Apr 7;11(1):1733.
A375 cells
0.1 nM to 10 nM
5 days
To evaluate the inhibitory effect of Binimetinib on A375 cells, results showed that Binimetinib has an inhibitory effect on A375 cells.
Mol Cancer Ther. 2023 Feb 1;22(2):227-239.
PC-9 cells
1 μM
7 or 14 days
To study the inhibitory effect of Binimetinib on PC-9 cells, 57 resistant ORFs were identified, revealing the central role of the MAP kinase pathway in resistance to EGFR inhibitors.
Cell Syst. 2020 Jan 22;10(1):52-65.e7.
A549 cells
1 µM
Investigate the effect of Binimetinib on the migration of KRAS-mutant cells, showing that Binimetinib reversibly inhibits cell migration.
Nat Commun. 2024 Sep 18;15(1):8178.
A431 cells
1 µM
Study the effect of Binimetinib on filopodia formation in A431 cells upon EGF stimulation, showing that Binimetinib significantly reduces filopodia formation.
Nat Commun. 2024 Sep 18;15(1):8178.
m82 (Brn2-hom) and m82-BRN2 mouse melanoma cells
10^-3 to 100 μM
9 days
To evaluate the effect of Binimetinib on colony formation in mouse melanoma cells and determine the IC50. Results showed that Brn2-het/hom cells are more sensitive to Binimetinib than WT cells.
Nat Commun. 2021 Jun 17;12(1):3707.
Binimetinib/比美替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
KitV558Δ;T669I/+ mice
Oral
10 mg/kg
Twice daily for 7 days
To evaluate the effect of Binimetinib on imatinib-resistant KitV558Δ;T669I/+ mouse tumors, results showed that both PI3K and MAPK signaling pathways were inhibited, and tumor cell proliferation was reduced.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):E8448-E8457
Mice
SK-N-AS xenograft model
Oral
3 mg/kg or 30 mg/kg
Twice daily, monitored continuously
Binimetinib significantly inhibited SK-N-AS tumor growth and increased survival
Nat Genet. 2015 Aug;47(8):864-71
Binimetinib/比美替尼 动物研究
Dose
Mice: min = 6 mg/kg[2] (p.o.), max = 30 mg/kg[4] (p.o.)
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