Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine(790) -> Methionine(790) Mutant

doi:10.1021/jm201591k

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	Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine(790) -> Methionine(790) Mutant
	Chang, Shaohua 1,2,4; Zhang, Lianwen 3,4; Xu, Shilin 1,2,4; Luo, Jinfeng 1,2; Lu, Xiaoyun 1,2; Zhang, Zhang 1,2; Xu, Tianfeng 1,2,4; Liu, Yingxue 1,2; Tu, Zhengchao 1,2; Xu, Yong 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-03-22
卷号	55 期号:6 页码:2711-2723
ISSN号	0022-2623
DOI	10.1021/jm201591k
文献子类	Article
英文摘要	The EGFR(T790M) mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFR(T790M)-related resistance. We have designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC50 values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model.
资助项目	National Basic Research Program of China[2010CB529706] ; National Basic Research Program of China[2009CB940904] ; National Natural Science Foundation[21072192] ; Key Project on Innovative Drug of Guangdong Province[2011A080501013] ; Strategic Collaborative Project of Guangdong Province[00000000] ; Chinese Academy of Sciences[00000000] ; Key Project on Innovative Drug of Guangzhou City[2009Z1-E911] ; Key Project on Innovative Drug of Guangzhou City[2010J-E551]
WOS关键词	TYROSINE KINASE INHIBITORS ; CELL LUNG-CANCER ; METASTATIC COLORECTAL-CANCER ; IRREVERSIBLE INHIBITORS ; DRUG DESIGN ; BCR-ABL ; EGFR ; RESISTANCE ; CETUXIMAB ; MUTATIONS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000301767000016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278147]
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	Ding, Ke
作者单位	1.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Peoples R China; 2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Inst Biol Chem, Guangzhou 510530, Peoples R China; 3.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China; 4.Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chang, Shaohua,Zhang, Lianwen,Xu, Shilin,et al. Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine(790) -> Methionine(790) Mutant[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(6):2711-2723.
APA	Chang, Shaohua.,Zhang, Lianwen.,Xu, Shilin.,Luo, Jinfeng.,Lu, Xiaoyun.,...&Ding, Ke.(2012).Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine(790) -> Methionine(790) Mutant.JOURNAL OF MEDICINAL CHEMISTRY,55(6),2711-2723.
MLA	Chang, Shaohua,et al."Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine(790) -> Methionine(790) Mutant".JOURNAL OF MEDICINAL CHEMISTRY 55.6(2012):2711-2723.