Design, synthesis and biological evaluation of potent epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

Cheng Wang; Xin Wang; Xiaoxue Wang; Baorui Tian; Sihe Zhang; Tianqi Wang; Yakun Ma; Yan Fan

doi:10.1016/j.bioorg.2023.107004

Design, synthesis and biological evaluation of potent epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

Bioorg Chem. 2024 Feb:143:107004. doi: 10.1016/j.bioorg.2023.107004. Epub 2023 Dec 6.

Authors

Cheng Wang¹, Xin Wang², Xiaoxue Wang², Baorui Tian², Sihe Zhang², Tianqi Wang², Yakun Ma², Yan Fan³

Affiliations

¹ Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
² School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
³ Eye Institute, Nankai University, 94 Weijin Road, Tianjin 300071, China; School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China. Electronic address: yanfan@nankai.edu.cn.

PMID: 38086238
DOI: 10.1016/j.bioorg.2023.107004

Abstract

In this study, we identified a newly synthesized compound 7o with potent inhibition on EGFR primary mutants (L858R, Del19) and drug-resistant mutant T790M with nanomolar IC₅₀ values. 7o showed strong antiproliferative effects against EGFR mutant-driven non-small cell lung cancer (NSCLC) cells such as H1975, PC-9 and HCC827, over cells expressing EGFR^WT. Molecular docking was performed to investigate the possible binding modes of 7o inside the binding site of EGFR^L858R/T790M and EGFR^WT. Analysis of cell cycle evidenced that 7o induced cell cycle arrest in G1 phases in the EGFR mutant cells, H1975 and PC-9, which resulted in decreased S-phase populations. Moreover, compound 7o induced cancer cell apoptosis in in vitro assays. In addition, 7o inhibited cellular phosphorylation of EGFR. In vivo, oral administration of 7o caused rapid tumor regression in H1975 xenograft model. Therefore, 7o might deserve further optimization as cancer treatment agent for EGFR mutant-driven NSCLC.

Keywords: Del19; EGFR; Inhibitor; L858R; T790M.

MeSH terms

Carcinoma, Non-Small-Cell Lung* / metabolism
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Lung Neoplasms* / metabolism
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors

Substances

ErbB Receptors
Protein Kinase Inhibitors
EGFR protein, human