A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles
文献类型：期刊论文
| 作者 | Xia, Guangxin2; Chen, Wenteng1; Zhang, Jing2; Shao, Jiaan1; Zhang, Yong2; Huang, Wei1; Zhang, Leduo2; Qi, Weixing1; Sun, Xing2; Li, Bojun2 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2014-12-11 |
| 卷号 | 57期号:23页码:9889-9900 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm5014659 |
| 文献子类 | Article |
| 英文摘要 | Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R)/(T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance. |
| WOS关键词 | CELL LUNG-CANCER ; GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITORS ; MEDICINAL CHEMISTRY ; DRUG-RESISTANCE ; GEFITINIB ; FLUORINE ; MUTATION ; DESIGN ; CHEMOTHERAPY |
| 资助项目 | National Natural Science Foundation of China[81273356] ; Program for Zhejiang Leading Team of ST Innovation[00000000] ; Osteoporosis and Breast Cancer Research Center, USA[00000000] ; China Postdoctoral Science Foundation[2014M550331] ; National Science and Technology Major Foundation of China[2010ZX09401-404] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000346321200013 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276807]  |
| 专题 | 药物化学研究室 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 | Yu, Yongping |
| 作者单位 | 1.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Zhejiang, Peoples R China; 2.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, Shanghai 201203, Peoples R China; 3.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 | Xia, Guangxin,Chen, Wenteng,Zhang, Jing,et al. A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles[J]. JOURNAL OF MEDICINAL CHEMISTRY,2014,57(23):9889-9900. |
| APA | Xia, Guangxin.,Chen, Wenteng.,Zhang, Jing.,Shao, Jiaan.,Zhang, Yong.,...&Yu, Yongping.(2014).A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles.JOURNAL OF MEDICINAL CHEMISTRY,57(23),9889-9900. |
| MLA | Xia, Guangxin,et al."A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles".JOURNAL OF MEDICINAL CHEMISTRY 57.23(2014):9889-9900. |
入库方式： OAI收割
来源：上海药物研究所
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