文献类型：期刊文献

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

作者：Dou, Dou[1,2];Zhang, Xingsen[1];Wang, Jie[1];Wumaier, Gulinuer[3];Qiao, Yunjin[1];Xie, Lijuan[1];Jiang, Wenzhe[1];Sha, Wenjie[1];Li, Wenjie[1];Mei, Wenyi[1];Zhang, Chen[1];He, Huan[1];Wang, Caolin[1];Wu, Lingkang[1];Diao, Yanyan[1];Zhu, Lili[1];Zhao, Zhenjiang[1];Chen, Zhuo[1];Xu, Yufang[1];Li, Shengqing[3];Li, Honglin[1,4]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Hebei Agr Univ, Coll Life Sci, Hebei Key Lab Anal & Control Zoonot Pathogen Micro, Baoding 071001, Peoples R China;[3]Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China;[4]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Shanghai 200062, Peoples R China

年份：2024

卷号：279

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001317560000001)】；

基金：The research was supported in part by the National Natural Science Foundation of China (grant 82425104, 82150208 and 81825020) , the National Key Research and Development Program (grant 2022YFC3400504 and 2022YFC3400501) , the Talents Introduction Plan of Hebei Agricultural University (YJ2023014) and the Fundamental Research Funds for the Hebei Province Universities and Colleges (KY2023041) and the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：NSCLC; EGFR; C797S mutation; Resistance; 4-Anilinoquinazoline

摘要：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 EGFR(L858R/T790M/C797S) with an IC50 value of 0.005 mu M, and exhibited anti-proliferation activity in BaF3-EGFR(L858R/T790M/C797S) cells with the IC50 value of 0.865 mu M. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFR(L858R/T790M/C797S) cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFR(L858R/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.