Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)-7-methoxyquinazoline derivatives as dual EGFR/c-Met inhibitors for the treatment of NSCLC

Sheng Tang; Chuanchuan Sun; Xintao He; Wenhui Gan; Linxiao Wang; Dan Qiao; Xinyu Guan; Shan Xu; Pengwu Zheng; Wufu Zhu

doi:10.1016/j.ejmech.2023.115939

Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)-7-methoxyquinazoline derivatives as dual EGFR/c-Met inhibitors for the treatment of NSCLC

Eur J Med Chem. 2024 Jan 5:263:115939. doi: 10.1016/j.ejmech.2023.115939. Epub 2023 Nov 15.

Authors

Sheng Tang¹, Chuanchuan Sun¹, Xintao He¹, Wenhui Gan¹, Linxiao Wang¹, Dan Qiao¹, Xinyu Guan¹, Shan Xu¹, Pengwu Zheng¹, Wufu Zhu²

Affiliations

¹ Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China.
² Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China. Electronic address: zhuwufu-1122@163.com.

PMID: 37984296
DOI: 10.1016/j.ejmech.2023.115939

Abstract

In non-small cell lung cancer (NSCLC) treatment, aberrant expression of c-mesenchymal-epithelial transition factor (c-Met) has been identified as a driving factor in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Unfortunately, none of the EGFR/c-Met dual-target inhibitors have successfully passed clinical trials. Hence, based on molecular docking analysis and combination principles of EGFR and c-Met inhibitors, three series of 4-(2-fluorophenoxy)-7-methoxyquinazoline derivatives as new EGFR/c-Met inhibitors were designed, synthesized, and evaluated for their biological activities. Among these compounds, TS-41 displayed the best inhibitory activity against EGFR^L858R and c-Met kinases, with an IC₅₀ value of 68.1 nM and 0.26 nM respectively. Moreover, it also showed excellent inhibitory activity on three NSCLC cell lines A549^-P, H1975 and PC-9 with IC₅₀ values ranging from 1.48 to 2.76 μM. Flow cytometry assays demonstrated that TS-41 induced apoptosis and cell cycle arrest of A549^-P cells in a concentration-dependent manner, corresponding to JC-1 staining assay results. Western blot analysis revealed that TS-41 significantly downregulated the phosphorylation of EGFR, c-Met, and downstream AKT at molecular level. Importantly, TS-41 exhibited potent in vivo anticancer efficacy in an A549^-P-bearing allograft nude mouse model at a dose of 60 mg/kg with a tumor growth inhibition rate of 55.3 % compared with Afatinib (46.4 %), as well as low hemolytic toxicity and organ toxicity. Molecular docking results showed that TS-41 was well embedded into the cavity of EGFR (PDB: 5GMP) and c-Met (PDB: 3LQ8) proteins, respectively. In summary, TS-41 is a high-efficiency and low-toxicity EGFR/c-Met inhibitor for the treatment of NSCLC and is worthy of further exploration.

Keywords: Allograft mouse model; EGFR-TKI resistance; EGFR/c-Met inhibitor; NSCLC; TS-41.

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
ErbB Receptors
Lung Neoplasms* / pathology
Mice
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use

Substances

ErbB Receptors
Protein Kinase Inhibitors