Affiliation:
1. School of Pharmacy, Jiangxi Science & Technology Normal University, China
2. Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, China
Abstract
Objectives:
The objective of this study is to identify dual-target inhibitors
against EGFR/c-Met through virtual screening, dynamic simulation, and biological activity
evaluation. This endeavor is aimed at overcoming the challenge of drug resistance induced
by L858R/T790M mutants.
Methods:
Active structures were gathered to construct sets of drug molecules. Next,
property filtering was applied to the drug structures within the compound library. Active
compounds were then identified through virtual screening and cluster analysis. Subsequently,
we conducted MTT antitumor activity evaluation and kinase inhibition assays
for the active compounds to identify the most promising candidates. Furthermore, AO
staining and JC-1 assays were performed on the selected compounds. Ultimately, the preferred
compounds underwent molecular docking and molecular dynamics simulation
with the EGFR and c-Met proteins, respectively.
Result:
The IC50 of T13074 was determined as 2.446 μM for EGFRL858R/T790M kinase and
7.401 nM for c-Met kinase, underscoring its potential in overcoming EGFRL858R/T790M resistance.
Additionally, T13074 exhibited an IC50 of 1.93 μM on the H1975 cell. Results
from AO staining and JC-1 assays indicated that T13074 induced tumor cell apoptosis in
a concentration-dependent manner. Notably, the binding energy between T13074 and
EGFR protein was found to be -90.329 ± 16.680 kJ/mol, while the binding energy with
c-Met protein was -139.935 ± 17.414 kJ/mol.
Conclusion:
T13074 exhibited outstanding antitumor activity both in vivo and in vitro,
indicating its potential utility as a dual-target EGFR/c-Met inhibitor. This suggests its
promising role in overcoming EGFR resistance induced by the L858R/T790M mutation.
Publisher
Bentham Science Publishers Ltd.