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2000
Volume 32, Issue 28
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

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.

Results

The IC 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 IC 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 and , 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.

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Virtual Screening, Molecular Dynamics Simulation, and Bioactivity Assessment Validate T13074 as a Dual-target EGFR/c-Met Inhibitor
Curr. Med. Chem. 32, 6092 (2025); https://doi.org/10.2174/0109298673305941240605050450
/content/journals/cmc/10.2174/0109298673305941240605050450
/content/journals/cmc/10.2174/0109298673305941240605050450
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  • Article Type:     Research Article
Keyword(s): biological activity evaluation; c-Met; drug discovery; dynamic simulation; EGFR resistance; ROC-based virtual screening

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