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Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors

文献类型：期刊论文

作者Hao, Yongjia1; Lyu, Jiankun1; Qu, Rong2,3; Sun, Deheng1; Zhao, Zhenjiang1; Chen, Zhuo1; Ding, Jian2; Xie, Hua2; Xu, Yufang1; Li, Honglin1
刊名SCIENTIFIC REPORTS
出版日期2017-06-19
卷号7
ISSN号2045-2322
DOI10.1038/s41598-017-04184-9
文献子类Article
英文摘要Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3] oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR(L858R/T790M). These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.
WOS关键词TYROSINE KINASE INHIBITORS ; CELL LUNG-CANCER ; GEFITINIB ; RESISTANCE ; ERLOTINIB ; CHEMOTHERAPY ; SENSITIVITY ; MUTATIONS ; DISCOVERY ; FAILURE
资助项目National Key Research and Development Program[2016YFA0502304] ; National Natural Science Foundation of China[21302054] ; National Natural Science Foundation of China[81230076] ; Shanghai Committee of Science and Technology[14431902100] ; Specialized Research Fund for the Doctoral Program of Higher Education[20130074110004] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020209]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000403650300073
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/272600]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Xie, Hua; Xu, Yufang; Li, Honglin
作者单位1.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Hao, Yongjia,Lyu, Jiankun,Qu, Rong,et al. Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors[J]. SCIENTIFIC REPORTS,2017,7.
APA Hao, Yongjia.,Lyu, Jiankun.,Qu, Rong.,Sun, Deheng.,Zhao, Zhenjiang.,...&Li, Honglin.(2017).Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors.SCIENTIFIC REPORTS,7.
MLA Hao, Yongjia,et al."Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors".SCIENTIFIC REPORTS 7(2017).

入库方式： OAI收割

来源：上海药物研究所

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