文献类型：期刊文献

英文题名：Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors

作者：Dou, Dou[1];Wang, Jie[1];Qiao, Yunjin[1];Wumaier, Gulinuer[2];Sha, Wenjie[1];Li, Wenjie[1];Mei, Wenyi[1];Yang, Tingyuan[1];Zhang, Chen[1];He, Huan[1];Wang, Caolin[1];Chu, Linna[1];Sun, Baihui[1];Su, Rongrong[1];Ma, Xiangyu[1];Gong, Mengdie[1];Xie, Lijuan[1];Jiang, Wenzhe[1];Diao, Yanyan[1];Zhu, Lili[1];Zhao, Zhenjiang[1];Chen, Zhuo[1];Xu, Yufang[1];Li, Shengqing[2];Li, Honglin[1]

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]Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China

年份：2022

卷号：244

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000914709200002)】；

基金：The research was supported by the National Natural Science Foundation of China (grants 81825020, 81803437, 82150208) , the Shanghai Committee of Science and Technology (grants 21S11907900 and 20S11901000) , Youth Natural Science Foundation project (grant No.82003596) and the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by 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：4-Anilinoquinazoline; Non-small cell lung cancer (NSCLC); Epidermal growth factor receptor (EGFR); Kinase inhibitor; Anti-proliferative activity

摘要：Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/ C797S (IC50 = 0.75 mu M) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 mu M) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.