C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant
文献类型：期刊论文
| 作者 | Xu, Tianfeng1; Peng, Ting2; Ren, Xiaomei1; Zhang, Lianwen1; Yu, Lei1; Luo, Jinfeng1; Zhang, Zhang1; Tu, Zhengchao1; Tong, Linjiang2; Huang, Zhaoru2 |
| 刊名 | MEDCHEMCOMM
 |
| 出版日期 | 2015 |
| 卷号 | 6期号:9页码:1693-1697 |
| ISSN号 | 2040-2503 |
| DOI | 10.1039/c5md00208g |
| 文献子类 | Article |
| 英文摘要 | The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d] pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFR(T790M) mutant. One of the most promising compounds, 9f, tightly binds to the EGFR(T790M) mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFR(T790M) mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities. |
| WOS关键词 | CELL LUNG-CANCER ; FACTOR RECEPTOR THREONINE(790) ; BIOLOGICAL EVALUATION ; ACQUIRED-RESISTANCE ; PHARMACOKINETIC PROPERTIES ; METHIONINE(790) MUTANT ; EGFR MUTATION ; PHASE-II ; T790M ; TRIAL |
| 资助项目 | National Natural Science Foundation of China[81425021] ; National Natural Science Foundation of China[8173080] ; National Natural Science Foundation of China[81321092] ; 100 Distinguished Scientist Award of Guangdong Province (Nanyue-Baijie Award)[00000000] ; Key Project on Innovative Drug of Guangdong Province[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000360639300015 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276707]  |
| 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 |
| 作者单位 | 1.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou 510530, Guangdong, Peoples R China; 2.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 | Xu, Tianfeng,Peng, Ting,Ren, Xiaomei,et al. C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant[J]. MEDCHEMCOMM,2015,6(9):1693-1697. |
| APA | Xu, Tianfeng.,Peng, Ting.,Ren, Xiaomei.,Zhang, Lianwen.,Yu, Lei.,...&Ding, Ke.(2015).C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant.MEDCHEMCOMM,6(9),1693-1697. |
| MLA | Xu, Tianfeng,et al."C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant".MEDCHEMCOMM 6.9(2015):1693-1697. |
入库方式： OAI收割
来源：上海药物研究所
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