2. Academic Validation
  3. Structure-guided discovery of a potent 2-aryl-4-aminoquinazoline-based inhibitor overcoming osimertinib resistance driven by EGFR C797S mutation in NSCLC

Structure-guided discovery of a potent 2-aryl-4-aminoquinazoline-based inhibitor overcoming osimertinib resistance driven by EGFR C797S mutation in NSCLC

  • Eur J Med Chem. 2026 Jul 5:311:118818. doi: 10.1016/j.ejmech.2026.118818.
Hao Chang 1,  Cheng Zhang 2,  Zhenyang Liang 3,  Fang Liu 4,  Yanhong Zhang 5,  Jiaxin Tian 6,  Zijie Xiao 7,  Haohua Chi 8,  Wenwen Du 9,  Shu Li 10,  Pengmei Li 11,  Renzhong Qiao 12,  Chao Li 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: 15933394316@163.com.
  • 2 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China; Beijing Key Laboratory of Critical Bridging Technologies for Chronic Disease Drug Development, Beijing, 100029, PR China. Electronic address: zhangcheng@zryhyy.com.cn.
  • 3 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: liang517813@163.com.
  • 4 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China. Electronic address: Liufang117117@126.com.
  • 5 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: yanhongZhang_ZYH@163.com.
  • 6 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: jxtian@bjtu.edu.cn.
  • 7 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: rex_zijie738@outlook.com.
  • 8 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China; Department of Pharmacy Administration and Clinical Pharmacy School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: 15524882303@163.com.
  • 9 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China. Electronic address: wenwendu523@126.com.
  • 10 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China. Electronic address: lishusdu@163.com.
  • 11 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China. Electronic address: lipengmei@yeah.net.
  • 12 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: qiao_group@163.com.
  • 13 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China. Electronic address: lichao@mail.buct.edu.cn.
PMID: 41950648 DOI: 10.1016/j.ejmech.2026.118818
Abstract

The C797S mutation in epidermal growth factor receptor (EGFR) is a major mechanism of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as Osimertinib, in non-small cell lung Cancer (NSCLC), creating an urgent need for effective therapeutic strategies. To address this challenge, we designed the structure-guided optimization of a 2-aryl-4-aminoquinazoline scaffold, leading to the discovery of a potent fourth-generation EGFR Inhibitor, compound 6g. The design focused on introducing flexible nitrogen-rich side chains to enable effective non-covalent interaction with the mutant Ser797 residue. Compound 6g exhibited superior activity against EGFRDel19/T790M/C797S with an enzymatic IC50 of 0.056 μM and potently inhibited the proliferation of resistant PC-9 cells (IC50 = 0.143 μM), outperforming the parent lead Angew-1 and Osimertinib by 6-fold and 16-fold, respectively. Further biological evaluation revealed that 6g effectively suppressed proliferation, migration, and induced Apoptosis in Osimertinib-resistant cells, concomitant with the inhibition of EGFR and its downstream Akt/MAPK signaling pathways. Favorable pharmacokinetic properties were observed in rats, with an absolute oral bioavailability of 22.33% and a high safety margin (selectivity index >500 in normal human lung epithelial BEAS-2B cells). In a PC-9Del19/T790M/C797S xenograft model, 6g achieved significant dose-dependent tumor growth inhibition (TGI: 47.3% at 5 mg/kg; 64.2% at 10 mg/kg), markedly surpassing Osimertinib (TGI: 16.07% at 10 mg/kg), with no observed significant toxicity. These results establish 6g as a promising fourth-generation EGFR-TKI candidate with potent activity, favorable pharmacokinetics, and a high safety profile, offering a potential therapeutic strategy against Osimertinib resistance driven by the C797S mutation.

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