The overexpression and activation of the Met receptor and its ligand HGF (hepatocyte growth factor) are associated with a wide variety of human malignancies, as well as the tumor invasion. Tepotinib is a selective c-Met inhibitor with IC50 value of 3nM (measured by kinase activity), over 200-fold against IRAK4, TrkA, Axl, IRAK1, Mer, TrkB and Ron. Exposure to Tepotinib resulted in inhibition of HGF-induced c-Met phosphorylation with IC50 of 6nM in A549 cells and a significant reduction of c-Met–constitutive phosphorylation with IC50 of 9nM in EBC-1 cells. The suppression of phosphorylation of the c-Met pathway, including Gab-1, Akt and Erk1/2, can also be observed. This kinase inhibition can also be observed in in vivo study as a single dose of 30mg/kg Tepotinib caused inhibition of c-Met auto-phosphorylation both in tumors derived from Hs746T xenograft mice, along with decreased cyclin D1 and inducing p27 expression, within 48h. As prediction, daily administration at dose of 6mg/kg significantly inhibited tumor growth in mice bearing human HGF-dependent pancreatic carcinoma cell line KP-4, while suppressed tumor growth at dose of 15mg/kg. In another model mice bearing subcutaneous tumors derived from the HGF-independent human lung cancer cell line EBC-1, the tumor growth by Tepotinib can be observed at dose of 25 or 50mg/kg, when the tumor suppression can be observed at dose of 200mg/kg[1].
To generate Tepotinib-resistant cell lines to study resistance mechanisms.
iScience. 2020 Nov 20;23(12):101832.
Hs746T
5 µM
12 monthourss
To generate Tepotinib-resistant cell lines to study resistance mechanisms.
iScience. 2020 Nov 20;23(12):101832.
SNU620
9 nM
48 hours
Tepotinib significantly induced apoptosis in SNU620 cells and significantly reduced the protein levels of phosphorylated and total c-MET, phosphorylated and total ERK, β-catenin, and c-MYC.
Int J Mol Sci. 2020 Aug 21;21(17):6027.
MKN45
7 nM
48 hours
Tepotinib significantly induced apoptosis in MKN45 cells and significantly reduced the protein levels of phosphorylated and total c-MET, phosphorylated and total ERK, β-catenin, and c-MYC.
Int J Mol Sci. 2020 Aug 21;21(17):6027.
KATO III
10 nM
48 hours
Tepotinib significantly induced apoptosis in KATO III cells but had minimal effects on the protein levels of phosphorylated and total c-MET, phosphorylated and total ERK, β-catenin, and c-MYC.
Int J Mol Sci. 2020 Aug 21;21(17):6027.
MHCC97H cells
10 nM
48 hours
To evaluate the antiproliferative activity of compound 8b, the results showed an IC50 value of 10 nM against MHCC97H cells.
Molecules. 2023 Jan 30;28(3):1304.
H358
0-18 µM
72 hours
To evaluate the antitumor effects of Tepotinib in combination with Omeprazole, the results showed that the combination significantly reduced cell viability.
Cell Commun Signal. 2024 Jun 12;22(1):324.
A549
0-7.9 µM
72 hours
To evaluate the antitumor effects of Tepotinib in combination with Omeprazole, the results showed that the combination significantly reduced cell viability.
Cell Commun Signal. 2024 Jun 12;22(1):324.
NCI-H460/TPT10 cells
1 and 3 µM
Tepotinib significantly enhanced the cytotoxicity of ABCG2 substrate drugs mitoxantrone and topotecan, reducing the IC50 values in drug-resistant cells.
Acta Pharm Sin B. 2022 May;12(5):2609-2618.
HEK293/ABCG2-WT cells
1 and 3 µM
Tepotinib significantly enhanced the cytotoxicity of ABCG2 substrate drugs mitoxantrone and topotecan, reducing the IC50 values in drug-resistant cells.
Acta Pharm Sin B. 2022 May;12(5):2609-2618.
HCCLM3 cells
0.013 µM
To evaluate the cytotoxicity of compound 8b against HCCLM3 cells, the results showed an IC50 value of 0.013 µM.
Molecules. 2023 Jan 30;28(3):1304.
LO2 cells
4.314 µM
To evaluate the cytotoxicity of compound 8b against LO2 cells, the results showed an IC50 value of 4.314 µM.
Molecules. 2023 Jan 30;28(3):1304.
97H cells (human liver cancer cells)
0.013 µM (IC50)
To evaluate the anti-tumor activity of the compounds, compound 31e showed the best inhibitory effect with an IC50 value of 26 nM
Molecules. 2019 Mar 25;24(6):1173.
Pc9 cells (human non-small cell lung cancer cells)
8.105 µM (IC50)
To evaluate the inhibitory activity of compound 31e against Pc9 cells, the IC50 value was 42.9 μM
Molecules. 2019 Mar 25;24(6):1173.
Hela cells (human epithelial cervical cancer cells)
11.22 µM (IC50)
To evaluate the inhibitory activity of compound 31e against Hela cells, the IC50 value was >50 μM
Molecules. 2019 Mar 25;24(6):1173.
SJSA1 cells (human osteosarcoma cells)
12.17 µM (IC50)
To evaluate the inhibitory activity of compound 31e against SJSA1 cells, the IC50 value was >50 μM
Molecules. 2019 Mar 25;24(6):1173.
LO2 cells (human normal liver cells)
10.33 µM (IC50)
To evaluate the inhibitory activity of compound 31e against LO2 cells, the IC50 value was >50 μM
Molecules. 2019 Mar 25;24(6):1173.
HLF cells (human embryonic lung fibroblast cells)
9.44 µM (IC50)
To evaluate the inhibitory activity of compound 31e against HLF cells, the IC50 value was >50 μM
Molecules. 2019 Mar 25;24(6):1173.
Tepotinib/特泊替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
MKN45 xenograft model
Oral
10 mg/kg
Once daily for 3 weeks
Tepotinib significantly inhibited tumor growth and increased ECAD expression while decreasing phosphorylated c-MET protein levels.
Int J Mol Sci. 2020 Aug 21;21(17):6027.
Mice
NSCLC xenograft models
Oral gavage
100 mg/kg
Daily for 32 days
To evaluate the antitumor effects of Tepotinib in combination with various EGFR TKIs in NSCLC xenograft models. The results showed that Tepotinib combined with EGFR TKIs effectively inhibited tumor growth, especially in models with high c-Met expression, where Tepotinib alone or in combination exhibited significant antitumor activity.
Am J Cancer Res. 2017 Apr 1;7(4):962-972
Nude mice
NCI-H460/TPT10 tumor xenograft model
Subcutaneous injection
30 mg/kg
Every 3 days until the end of the experiment
Tepotinib significantly enhanced the antitumor effect of topotecan in drug-resistant tumors, increasing intratumoral drug accumulation.
Acta Pharm Sin B. 2022 May;12(5):2609-2618.
Nu/Nu mice
H358 cell-derived tumor xenograft model
Subcutaneous injection
5 mg/kg
Once daily for three weeks
To evaluate the in vivo antitumor effects of Tepotinib in combination with Omeprazole, the results showed that the combination significantly inhibited tumor growth.
Cell Commun Signal. 2024 Jun 12;22(1):324.
Mice
EBC-1 xenograft model
Oral
5 mg/kg
Once daily, continuous treatment
To evaluate the inhibitory effect of Tepotinib in combination with SHP2 inhibitor on tumor growth.
iScience. 2020 Nov 20;23(12):101832.
Rat
Sprague‒Dawley rats
Oral
50 mg/kg
Single dose
To study the drug-drug interaction between Tepotinib and naringenin, the results showed that naringenin significantly increased the plasma exposure of Tepotinib and decreased its clearance rate.
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