Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

doi:10.1021/acs.jmedchem.8b00346

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	Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
	Hao, Yongjia 1,2; Lyu, Jiankun 1; Qu, Rong 3; Tong, Yi 1; Sun, Deheng 1; Feng, Fang 3; Tong, Linjiang 3; Yang, Tingyuan 1; Zhao, Zhenjiang 1; Zhu, Lili 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-07-12
卷号	61 期号:13 页码:5609-5622
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.8b00346
文献子类	Article
英文摘要	First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFR(L8S8R/T790M) and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFR(L8S8R/T790M) inhibitors.
资助项目	National Key Research and Development Program[2016YEA0502304] ; Shanghai Committee of Science and Technology[14431902100] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[U1501501] ; National Program for Special Supports of Eminent Professionals[00000000] ; National Program for Support of Top-notch Young Professionals[00000000]
WOS关键词	CELL LUNG-CANCER ; TYROSINE KINASE INHIBITORS ; IRREVERSIBLE INHIBITORS ; MUTANT ; GEFITINIB ; ERLOTINIB ; DISCOVERY ; APPROVAL ; OPTIMIZATION ; CHEMOTHERAPY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000439006100011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279659]
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	Xu, Yufang; Xie, Hua; Li, Honglin
作者单位	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.Guizhou Univ Chinese Med, Sch Pharm, Guiyang 550025, Guizhou, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hao, Yongjia,Lyu, Jiankun,Qu, Rong,et al. Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(13):5609-5622.
APA	Hao, Yongjia.,Lyu, Jiankun.,Qu, Rong.,Tong, Yi.,Sun, Deheng.,...&Li, Honglin.(2018).Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.JOURNAL OF MEDICINAL CHEMISTRY,61(13),5609-5622.
MLA	Hao, Yongjia,et al."Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation".JOURNAL OF MEDICINAL CHEMISTRY 61.13(2018):5609-5622.