Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors

  • Eur J Med Chem. 2024 Sep 12:279:116858. doi: 10.1016/j.ejmech.2024.116858.
Dou Dou  1 ,  Xingsen Zhang  2 ,  Jie Wang  2 ,  Gulinuer Wumaier  3 ,  Yunjin Qiao  2 ,  Lijuan Xie  2 ,  Wenzhe Jiang  2 ,  Wenjie Sha  2 ,  Wenjie Li  2 ,  Wenyi Mei  2 ,  Chen Zhang  2 ,  Huan He  2 ,  Caolin Wang  2 ,  Lingkang Wu  2 ,  Yanyan Diao  2 ,  Lili Zhu  2 ,  Zhenjiang Zhao  2 ,  Zhuo Chen  4 ,  Yufang Xu  5 ,  Shengqing Li  6 ,  Honglin Li  7
Affiliations
  • 1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China.
  • 2. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 3. Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 4. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
  • 5. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
  • 6. Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 7. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
PMID: 39278125 DOI: 10.1016/j.ejmech.2024.116858
Abstract

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung Cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFRL858R/T790M/C797S with an IC50 value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFRL858R/T790M/C797S cells with the IC50 value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell Apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFRL858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFRL858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR Inhibitor for further development in overcoming the EGFR-C797S resistance mutation.

Keywords
4-Anilinoquinazoline; C797S mutation; EGFR; NSCLC; Resistance.
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