Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma
文献类型：期刊论文
| 作者 | Wang, Qi1,4; Dai, Yang3; Ji, Yinchun3; Shi, Huanyu1,4; Guo, Zuhao1,4; Chen, Danqi1 ; Chen, Yuelei1; Peng, Xia3; Gao, Yinglei3; Wang, Xin1
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| 刊名 | European journal of medicinal chemistry
 |
| 出版日期 | 2018-12-07 |
| 卷号 | 163页码:671-689 |
| ISSN号 | 1768-3254 |
| DOI | 10.1016/j.ejmech.2018.12.015 |
| 文献子类 | Article |
| 英文摘要 | Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/266292]  |
| 专题 | 新药研究国家重点实验室 药理学第一研究室 |
| 通讯作者 | Ai, Jing; Xiong, Bing |
| 作者单位 | 1.Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; 2.University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China 3.Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; 4.University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China; |
| 推荐引用方式 GB/T 7714 | Wang, Qi,Dai, Yang,Ji, Yinchun,et al. Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma[J]. European journal of medicinal chemistry,2018,163:671-689. |
| APA | Wang, Qi.,Dai, Yang.,Ji, Yinchun.,Shi, Huanyu.,Guo, Zuhao.,...&Xiong, Bing.(2018).Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma.European journal of medicinal chemistry,163,671-689. |
| MLA | Wang, Qi,et al."Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma".European journal of medicinal chemistry 163(2018):671-689. |
入库方式： OAI收割
来源：上海药物研究所
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