Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors
文献类型：期刊论文
| 作者 | Li, Chunpu5,6; Dai, Yang4; Kong, Xiangtai6; Wang, Bao6; Peng, Xia4; Wu, Hengbo3,6; Shen, Yanyan4; Yang, Yanchen2,6; Ji, Yinchun4; Wang, Danyi3,4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2023-03-09 |
| 卷号 | 66期号:5页码:3226-3249 |
| DOI | 10.1021/acs.jmedchem.2c01507 |
| 文献子类 | Article |
| 英文摘要 | Small-molecule fibroblast growth factor receptor (FGFR) inhibitors have emerged as a promising antitumor therapy. Herein, by further optimizing the lead compound 1 under the guidance of molecular docking, we obtained a series of novel covalent FGFR inhibitors. After careful structure-activity relation-ship analysis, several compounds were identified to exhibit strong FGFR inhibitory activity and relatively better physicochemical and pharmacokinetic properties compared with those of 1. Among them, 2e potently and selectively inhibited the kinase activity of FGFR1-3 wildtype and high-incidence FGFR2-N549H/K-resist-ant mutant kinase. Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression. |
| WOS关键词 | SELECTIVE INHIBITOR ; DOSE-ESCALATION ; PHASE-I ; RESISTANCE ; CANCER ; STRATEGIES ; MUTATIONS ; DISCOVERY ; POTENT |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000936121800001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309696]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zheng, Mingyue; Ai, Jing; Liu, Hong |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 2.China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 5.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; 6.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 | Li, Chunpu,Dai, Yang,Kong, Xiangtai,et al. Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(5):3226-3249. |
| APA | Li, Chunpu.,Dai, Yang.,Kong, Xiangtai.,Wang, Bao.,Peng, Xia.,...&Liu, Hong.(2023).Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors.JOURNAL OF MEDICINAL CHEMISTRY,66(5),3226-3249. |
| MLA | Li, Chunpu,et al."Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors".JOURNAL OF MEDICINAL CHEMISTRY 66.5(2023):3226-3249. |
入库方式： OAI收割
来源：上海药物研究所
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