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The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations.

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资源类型：
Pubmed体系：
作者：
Xia Zhenqiang[1,2,3] ; Huang Ridong[1,2,3] ; Zhou Xinglong[1,2,3] ; Chai Yingying[1,2,3] ; Chen Hai[1,2,3] ; Ma Lingling[1,2,3] ; Yu Quanwei[1,2,3] ; Li Ying[1,2,3] ; Li Weimin[1,2,3,*2] ; He Yang[1,2,3,*1] ;
机构： [1]Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China [2]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China [3]Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China
出处：
DOI： 10.1016/j.ejmech.2021.113711
ISSN：

摘要：
EGFR mutations are an ongoing challenge in the treatment of NSCLC, and demand continuous updating of EGFR TKI drug candidates. Pyrrolopyrimidines are one group of versatile scaffolds suitable for tailored drug development. However not many precedents of this type of pharmacophore have been investigated in the realm of third generation of covalent EGFR-TKIs. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives able to block mutant EGFR activity in a covalent manner were synthesized, through optimized Buchwald-Hartwig C-N cross coupling reactions. Their preliminary bioactivity and corresponding inhibitory mechanistic pathways were investigated at molecular and cellular levels. Several compounds exhibited increased biological activity and enhanced selectivity compared to the control compound. Notably, compound 12i selectively inhibits HCC827 cells harboring the EGFR activating mutation with up to 493-fold increased efficacy compared to in normal HBE cells. Augmented selectivity was also confirmed by kinase enzymatic assay, with the test compound selectively inhibiting the T790 M activating mutant EGFRs (IC50 values of 0.21 nM) with up to 104-fold potency compared to the wild-type EGFR (IC50 values of 22 nM). Theoretical simulations provide structural evidence of selective kinase inhibitory activity. Thus, this series of pyrrolo[2,3-d]pyrimidine derivatives could serve as a starting point for the development of new EGFR-TKIs.Copyright © 2021 Elsevier Masson SAS. All rights reserved.

基金：
China Patent Application No. CN 111848631 A, 2020
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]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]Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China [2]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China [3]Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China [2]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China [3]Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China [*1]West China Hospital, Sichuan University, Chengdu, 610041, PR China. [*2]West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China.
推荐引用方式(GB/T 7714)：
Xia Zhenqiang,Huang Ridong,Zhou Xinglong,et al.The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations.[J].European journal of medicinal chemistry.2021,224:113711.doi:10.1016/j.ejmech.2021.113711.
APA：
Xia Zhenqiang,Huang Ridong,Zhou Xinglong,Chai Yingying,Chen Hai...&He Yang.(2021).The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations..European journal of medicinal chemistry,224,
MLA：
Xia Zhenqiang,et al."The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations.".European journal of medicinal chemistry 224.(2021):113711

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