EGFR is a member of epidermal growth factor receptor (HER) family. It is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR gene mutations and protein overexpression can both activate pathways (Protein Tyrosine Kinase/RTK). Pelitinib (EKB-569) is an irreversible EGFR inhibitor by inhibiting phosphorylation. It can also slightly inhibit SRC, MEK / ERK and erbB2. The inhibitory effect of Pelitinib on EGFR was higher than that of Src, MEK/ERK, Cdk4, c-Met, Raf and ErbB2. The IC50 for EGFR is 32-fold lower than the IC50 for ErbB2. The IC50s of Pelitinib in inhibiting NHEK, A431, MDA-468 cells proliferation were 61, 125 and 260 nM, respectively [3]. The result of in-cell western assay showed that Pelitinib inhibited endogenous total cellular tyrosine and endogenous ERK1/2 phosphorylation in a dose-dependent manner in A431 cells. Pelitinib at 1000 nM can inhibit EGFR and ERK phosphorylation significantly after 60 min incubation [4]. In vitro studies determined that Pelitinib at 100nM and 1,000nM inhibited circa 70% SS1-induced pERK1/2 relative to untreated SS1-stimulated in A431 cells. In vivo , studies showed that Pelitinib treatment resulted in a significant reduction (p < 0.05) in glandular herniations which were present in two of eight (25%) of H. pylori-infected Pelitinib treated gerbils [5].
作用机制
Pelitinib is an irreversible EGFR inhibitor by inhibiting phosphorylation.
Pelitinib/培利替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293
1, 2, 5 μM
3 h
To study the inhibition kinetics of pelitinib on ABCB1- and ABCG2-mediated topotecan efflux. Results showed that pelitinib is a competitive inhibitor of both ABCB1 and ABCG2.
Br J Pharmacol. 2015 Aug;172(16):4089-106.
A549
3 μM
48 h
To evaluate the effect of pelitinib in combination with topotecan on apoptosis in A549 cells after hyperthermia exposure. Results showed that pelitinib significantly enhanced the apoptotic effect of topotecan after hyperthermia.
Br J Pharmacol. 2015 Aug;172(16):4089-106.
mouse tracheal epithelial cells
50 µM
7 days
To study the effect of PI3K inhibitor on the survival of ciliated epithelial cells, results showed that PI3K inhibitor induced apoptosis of ciliated cells.
J Clin Invest. 2006 Feb;116(2):309-21.
mouse tracheal epithelial cells
0.3 µM
7 days
To study the effect of EKB-569 on the survival of ciliated epithelial cells, results showed that EKB-569 induced apoptosis of ciliated cells.
J Clin Invest. 2006 Feb;116(2):309-21.
SNU449 cells
0.2, 0.5, 1, 2 μM
48 h
To evaluate the inhibitory effect of EKB-569 on the migration of SNU449 cells. The results showed that EKB-569 significantly inhibited wound healing of SNU449 cells.
BMC Cancer. 2023 Jul 27;23(1):703.
Hep3B cells
0.2, 0.5, 1, 2 μM
48 h
To evaluate the inhibitory effect of EKB-569 on the migration of Hep3B cells. The results showed that EKB-569 significantly inhibited wound healing of Hep3B cells.
BMC Cancer. 2023 Jul 27;23(1):703.
Huh7 cells
0.2, 0.5, 1, 2 μM
48 h
To evaluate the inhibitory effect of EKB-569 on the migration and invasion of Huh7 cells. The results showed that EKB-569 significantly inhibited wound healing and invasion of Huh7 cells, and reduced the activities of MMP-2 and MMP-9.
BMC Cancer. 2023 Jul 27;23(1):703.
Pelitinib/培利替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Virus-induced airway epithelial remodeling model
Orally
20 mg/kg
Once daily for 11 days
To study the effect of EKB-569 on virus-induced epithelial remodeling, results showed that EKB-569 prevented increases in ciliated and goblet cells.
J Clin Invest. 2006 Feb;116(2):309-21.
BALB/c mice
4T1 tumor model
Oral
5 mg/kg, 10 mg/kg, 20 mg/kg
Once daily for 14 days
To evaluate the anti-tumor effects of pelitinib in the 4T1 tumor model, results showed that pelitinib significantly inhibited tumor volume and weight, and suppressed M2 macrophage polarization and the EMT process
J Pharm Anal. 2024 Aug;14(8):100975
C57BL/6J mice
Wild-type mice
Oral
150 mg/kg of food
Daily for 90 days
To evaluate the effects of EKB-569 on cardiac function and pathology. Results showed that EKB-569 caused loss, thinning of the left ventricular wall, changes in cardiac function, and increased cardiac fibrosis and apoptotic cell numbers.
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