Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors
文献类型：期刊论文
| 作者 | Xiao, Qiang2; Qu, Rong1; Gao, Dingding2; Yan, Qi2; Tong, Linjiang1; Zhang, Wei2; Ding, Jian1 ; Xie, Hua1; Li, Yingxia2
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-06-15 |
| 卷号 | 24期号:12页码:2673-2680 |
| 关键词 | 5-(Methylthio)pyrimidine derivatives Mutant selective inhibitors Epidermal growth factor inhibitor NSCLC Structure-based drug design |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2016.04.032 |
| 文献子类 | Article |
| 英文摘要 | To overcome the drug-resistance of first generation EGFR inhibitors and the nonselective toxicities of second generation inhibitors among NSCLC patients, a series of 5-(methylthio)pyrimidine derivatives were discovered as novel EGFR inhibitors, which harbored not only potent enzymatic and antiproliferative activities against EGFR(L858R/T790M) mutants, but good selectivity over wide-type form of the receptor. This goal was achieved by employing structure-based drug design and traditional optimization strategies, based on WZ4002 and CO1686. These derivatives inhibited the enzymatic activity of EGFR(L858R/T790M) mutants with IC50 values in subnanomolar ranges, while exhibiting hundreds of fold less potency on EGFR(WT). These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFR(WT). The EGFR kinase inhibitory and antiproliferative activities were further validated by Western blot analysis for activation of EGFR and the downstream signaling in cancer cells. (C) 2016 Elsevier Ltd. All rights reserved. |
| WOS关键词 | CELL LUNG-CANCER ; TYROSINE KINASE INHIBITORS ; PAN-ERBB INHIBITOR ; ACQUIRED-RESISTANCE ; T790M ; MUTATIONS ; GEFITINIB ; AZD9291 ; TKI |
| 资助项目 | National Natural Science Foundation of China[81473075] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000376727800008 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275999]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Xie, Hua; Li, Yingxia |
| 作者单位 | 1.Chinese Acad Sci, Inst Mat Med, Shanghai 201203, Peoples R China 2.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Xiao, Qiang,Qu, Rong,Gao, Dingding,et al. Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2016,24(12):2673-2680. |
| APA | Xiao, Qiang.,Qu, Rong.,Gao, Dingding.,Yan, Qi.,Tong, Linjiang.,...&Li, Yingxia.(2016).Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,24(12),2673-2680. |
| MLA | Xiao, Qiang,et al."Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 24.12(2016):2673-2680. |
入库方式： OAI收割
来源：上海药物研究所
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