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