Extracellular signal-regulated kinases (ERKs) are protein kinase intracellular signaling molecules that participate in Ras-Raf-MEK-ERK signal transduction cascade, which is related with the regulation of various processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription[3]. VX-11e is an ERK inhibitor with IC50 value of 17 nM and 15 nM on ERK1 and ERK2, respectively[4]. While VX-11e was tested for cytotoxic activity on A549 and DM122, they EC50 value is 770 nM and 370 nM after four days of incubation. The ERK1/2 phosphorylation level analyzed by western blot assay showed enhancement at both 0.5 μM and 2μM of vx-11e[4]. In human melanoma RPDX tumor expanded NSG mice, the vx-11e was given 50 mg/kg BID for 2 weeks. VX-11 could inhibit the tumor growth significantly compared to control, and the PI3K expression level measured by western blot assay was inhibited in the tumor tissue[5].
作用机制
The vx-11e can bind with the inactive, unphosphorylated and active, phosphorylated ERK2. The equilibrium between the T and R-state conformers formed by the inhibitor with the inactive and active enzyme is strongly shifts to favor the R form. Thus, the allosteric properties of ERK2 endow the active form of the kinase with a novel capability of being inhibited through mechanisms involving conformational selection[6].
VX-11e 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SH-SY5Y cells
50 nM
24 hours
VX-11e reduced unphosphorylated ERK1/2 levels in SH-SY5Y cells but not in HCT-116 cells.
J Biol Chem. 2022 Aug;298(8):102226.
MOLM-14 cells
0.625 to 40 µM
24 hours
VX-11e significantly inhibited the proliferation of MOLM-14 cells and reduced ERK activation.
Apoptosis. 2019 Dec;24(11-12):849-861.
K562 cells
0.625 to 40 µM
24 hours
VX-11e significantly inhibited the proliferation of K562 cells and reduced ERK activation.
Apoptosis. 2019 Dec;24(11-12):849-861.
REH cells
0.625 to 40 µM
24 hours
VX-11e significantly inhibited the proliferation of REH cells and reduced ERK activation.
Apoptosis. 2019 Dec;24(11-12):849-861.
MOLT-4 cells
0.625 to 40 µM
24 hours
VX-11e significantly inhibited the proliferation of MOLT-4 cells and reduced ERK activation.
Apoptosis. 2019 Dec;24(11-12):849-861.
SiHa cells
10 µM
48 hours
To validate the effect of VX-11e on CKAP2 overexpression-induced cell migration and invasion, results showed that VX-11e significantly inhibited CKAP2 overexpression-induced cell migration and invasion.
Sci Rep. 2017 May 18;7(1):2117.
HCT-116 cells
39 nM
96 hours
VX-11e inhibits ERK in HCT-116 cells at a slightly higher concentration than ulixertinib (39 nM vs 32 nM) but exerts toxicity at a considerably lower concentration (12 nM vs 36 nM).
J Biol Chem. 2022 Aug;298(8):102226.
U937 cells
5.7 µM
96 hours
VX-11e has an IC50 value of 5.7 μM in U937 cells, significantly higher than in other cell lines, indicating lower sensitivity in U937 cells.
J Biol Chem. 2022 Aug;298(8):102226.
VX-11e 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
Human melanoma RPDX tumors
Oral gavage
50 mg/kg
BID，14 days
Demonstrated effective outcomes in vivo when combined with BRAF and MEK inhibitors.
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