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Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.

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资源类型：
Pubmed体系：
作者：
Wang Cheng[1,4] ; Wang Xin[1] ; Huang Zhi[1] ; Wang Tianqi[1] ; Nie Yongwei[1] ; Yang Shengyong[3] ; Xiang Rong[1,2,*1] ; Fan Yan[1,2,*1] ;
机构： [1]School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China [3]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [4]Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
出处：
DOI： 10.1016/j.ejmech.2022.114381
ISSN：

关键词： EGFR Inhibitor C797S NSCLC

摘要：
The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung cancer (NSCLC). In this study, we identified a potent and oral EGFRL858R/T790M/C797S tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFRL858R/T790M/C797S mutant with IC50 value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFRL858R/T790M/C797S and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

基金：
National Natural Science Foundation of China (81903099), the National Key Research and Development Program of China (2018YFE0114300) and the National Natural Science Foundation of China (81972882).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 药物化学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [4]Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
通讯作者：
通讯机构： [1]School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China [*1]School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
推荐引用方式(GB/T 7714)：
Wang Cheng,Wang Xin,Huang Zhi,et al.Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.[J].European journal of medicinal chemistry.2022,237:114381.doi:10.1016/j.ejmech.2022.114381.
APA：
Wang Cheng,Wang Xin,Huang Zhi,Wang Tianqi,Nie Yongwei...&Fan Yan.(2022).Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment..European journal of medicinal chemistry,237,
MLA：
Wang Cheng,et al."Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.".European journal of medicinal chemistry 237.(2022):114381

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