Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design
文献类型：期刊论文
| 作者 | Wang, Yulan1; Dai, Yang1; Wu, Xiaowei2; Li, Fei1,3; Liu, Bo1; Li, Chunpu1,2; Liu, Qiufeng2; Zhou, Yuanyang1,4; Wang, Bao2,5; Zhu, Mingrui1 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-08-22 |
| 卷号 | 62期号:16页码:7473-7488 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.9b00510 |
| 通讯作者 | Liu, Hong(hliu@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn) |
| 英文摘要 | Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery. |
| WOS关键词 | SELECTIVE INHIBITOR ; IRREVERSIBLE INHIBITORS ; METABOLISM PREDICTION ; ANTITUMOR-ACTIVITY ; FGFR ; CANCER ; POTENT ; CLEARANCE ; DOCKING ; BINDING |
| 资助项目 | National Natural Science Foundation of China[81773634] ; National Natural Science Foundation of China[81773762] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Pro-gram of the Chinese Academy of Sciences[XDA12050201] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Pro-gram of the Chinese Academy of Sciences[XDA12050401] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000482545600009 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/288887]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Hong; Ai, Jing; Zheng, Mingyue |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 3.Shanghai Univ, Sch Chem, 99 ShangDa Rd, Shanghai 200444, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yulan,Dai, Yang,Wu, Xiaowei,et al. Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(16):7473-7488. |
| APA | Wang, Yulan.,Dai, Yang.,Wu, Xiaowei.,Li, Fei.,Liu, Bo.,...&Zheng, Mingyue.(2019).Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design.JOURNAL OF MEDICINAL CHEMISTRY,62(16),7473-7488. |
| MLA | Wang, Yulan,et al."Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design".JOURNAL OF MEDICINAL CHEMISTRY 62.16(2019):7473-7488. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。