The human MET proto-oncogene encodes the MET kinase, also known as HGF receptor. The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. LY2801653 is designed as a potent, orally bioavailable c-Met inhibitor. The mean IC50 value of LY2801653 for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells was 35.2 ± 6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells was 59.2 nM. LY2801653, in the concentration range of 0.01–10 μM, completely blocked the HGF-induced DU-145 cell scattering. LY2801653 also demonstrated potent anti-proliferative activity in cell lines with MET gene amplification (MKN45, Hs746T and H1993). MET target inhibition studies to assess activity of LY2801653 were undertaken in S114 xenograft tumors created through subcutaneous implantation of S114 cells, a murine cell line engineered to express both human MET and HGF. MET phosphorylation was inhibited by 98 % with a single dose of 50-mg/kg LY2801653 for 2 h. Furthermore, LY2801653 treatment inhibited MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 of 7.4 mg/kg [3].
作用机制
LY2801653 bound MET is in an inactive form with the activation loop DFG motif adopting a DFG-out conformation .
Merestinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
rSUM149 cells
100 nM and 1000 nM
24 h
Merestinib significantly inhibited the pERK and peIF4E pathways in rSUM149 cells, reduced CDK1, XIAP, and SOD2 protein levels, and induced cell death.
NPJ Breast Cancer. 2024 Jul 29;10(1):65.
SUM149 cells
100 nM and 1000 nM
24 h
Merestinib significantly inhibited the pERK and peIF4E pathways in SUM149 cells, reduced CDK1, XIAP, and SOD2 protein levels.
NPJ Breast Cancer. 2024 Jul 29;10(1):65.
U87
1 μM
1 h
Merestinib blocked phosphorylation of eIF4E, indicating inhibition of MNK signaling.
Mol Cancer Res. 2016 Oct;14(10):984-993.
83Mes
1 μM
1 h
Merestinib blocked phosphorylation of eIF4E, indicating inhibition of MNK signaling.
Mol Cancer Res. 2016 Oct;14(10):984-993.
GBM43
1 μM
1 h
Merestinib blocked phosphorylation of eIF4E, indicating inhibition of MNK signaling.
Mol Cancer Res. 2016 Oct;14(10):984-993.
U87 cells
1 μM
24 h
Merestinib treatment resulted in a decrease in polysomal peak area, indicating inhibition of global protein synthesis.
Mol Cancer Res. 2016 Oct;14(10):984-993.
83Mes cells
1 μM and 10 μM
24 h
Merestinib treatment resulted in a decrease in polysomal peak area, indicating inhibition of global protein synthesis.
Mol Cancer Res. 2016 Oct;14(10):984-993.
GBM43 cells
1 μM and 10 μM
24 h
Merestinib treatment resulted in a decrease in polysomal peak area, indicating inhibition of global protein synthesis.
Mol Cancer Res. 2016 Oct;14(10):984-993.
Ba/F3 cells
100 nM or 500 nM
To evaluate the inhibitory effect of Merestinib at different concentrations on resistant clones of Ba/F3 cells.
Mol Cancer Ther. 2022 Feb;21(2):322-335.
Merestinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Intracranial xenograft GBM model
Oral
12 mg/kg
Twice daily for 2 weeks
Merestinib significantly prolonged survival and inhibited MNK signaling.
Mol Cancer Res. 2016 Oct;14(10):984-993.
Nude mice
Intracranial xenograft GBM model
Oral
12 mg/kg
Twice daily for 2 weeks
Merestinib significantly prolonged survival in nude mice and inhibited tumor growth.
Mol Cancer Res. 2016 Oct;14(10):984-993.
SHO mice
TPR-MET mutant Ba/F3 cell xenograft model
Oral gavage
24 mg/kg
Once daily for 18 days
To evaluate the tumor growth inhibitory effect of Merestinib in combination with Capmatinib on TPR-MET mutant Ba/F3 cell xenograft model. The combination treatment significantly reduced tumor growth.
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