2. Academic Validation
  3. Pan-EGFR inhibitor targeting EGFR 19del, L858R/T790M and C797S triple-mutations: Design, synthesis, and pharmacological evaluation

Pan-EGFR inhibitor targeting EGFR 19del, L858R/T790M and C797S triple-mutations: Design, synthesis, and pharmacological evaluation

  • Bioorg Chem. 2025 Sep:164:108878. doi: 10.1016/j.bioorg.2025.108878.
Luhong Wang 1,  Fei Xie 2,  Shujing Li 3,  Guanglu Guo 2,  Qiyu Song 2,  Xinyu Yuan 4,  Jie Kang 3,  Yulin Li 3,  Aoli Wang 5,  Huijian Wu 6,  Youjun Xu 7
Affiliations

Affiliations

  • 1 Faculty of Medicine, Dalian University of Technology, Liaoning Province Key Laboratory of Protein Modification and Disease, Dalian 116024, China; School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Faculty of Medicine, Dalian University of Technology, Liaoning Province Key Laboratory of Protein Modification and Disease, Dalian 116024, China.
  • 4 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
  • 5 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China. Electronic address: kitty198702@hmfl.ac.cn.
  • 6 Faculty of Medicine, Dalian University of Technology, Liaoning Province Key Laboratory of Protein Modification and Disease, Dalian 116024, China. Electronic address: wuhj@dlut.edu.cn.
  • 7 School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: xuyoujun@syphu.edu.cn.
PMID: 40876225 DOI: 10.1016/j.bioorg.2025.108878
Abstract

Acquired resistance mediated by the EGFR C797S mutation remains a critical barrier in the treatment of non-small cell lung Cancer (NSCLC), reducing the effectiveness of third-generation EGFR inhibitors that target T790M-containing mutations. In this study, novel 2,4-diarylamino pyrimidine derivatives were identified and characterized as pan-mutant EGFR tyrosine kinase inhibitors. Compound D10 potently inhibited EGFR19del/T790M/C797S mutant (IC50 = 1.19 nM) and suppressed the proliferation of Ba/F3 cells harboring EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 0.192 and 1.303 μM. D10 also showed strong effects on the proliferation of EGFR19del and EGFRL858R/T790M mutants with IC50 values of 0.69 nM and 0.242 μM, respectively. D10 exhibited over 100-fold selectivity for mutant over wild-type (WT) EGFR and displayed low toxicity to normal Ba/F3 cells. Docking study demonstrated that D10 occupied the active site of EGFR and formed important hydrogen bonds with Lys728 and Ser797. The molecular dynamics simulations indicated that the binding free energy of D10 was -31.98 kcal/mol. Mechanistic studies revealed that D10 significantly inhibited cell migration, induced Apoptosis in NSCLC cells. What's more, D10 inhibited EGFR and ERK1/2 autophosphorylation. In vivo studies demonstrated that D10 exhibited antitumor efficacy in NSCLC and Ba/F3 xenograft models, with favorable pharmacokinetics (53.30 % oral bioavailability) and low toxicity.

Keywords

Lysine; Mutation; NSCLC; Resistance; pan-EGFR inhibitor.

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