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

doi:10.1038/s41598-017-04184-9

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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
	Hao, Yongjia 1; Lyu, Jiankun 1; Qu, Rong 2,3; Sun, Deheng 1; Zhao, Zhenjiang 1; Chen, Zhuo 1; Ding, Jian2 ; Xie, Hua2 ; Xu, Yufang 1; Li, Honglin 1
刊名	SCIENTIFIC REPORTS
	2017-06-19
卷号	7
ISSN号	2045-2322
DOI	10.1038/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.
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关键词	TYROSINE KINASE INHIBITORS ; CELL LUNG-CANCER ; GEFITINIB ; RESISTANCE ; ERLOTINIB ; CHEMOTHERAPY ; SENSITIVITY ; MUTATIONS ; DISCOVERY ; FAILURE
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000403650300073
内容类型	期刊论文
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).