中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

文献类型:期刊论文

作者Yang, Bowen1,2; Zhang, Haoran3; Li, Na2,4; Gao, Lixin5; Jiang, Hong1,2; Kan, Weijuan5; Yuan, Haoxing3; Li, Jia4,5; Zhao, Dongmei1; Xiong, Bing2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-11-17
页码19
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01334
通讯作者Zhao, Dongmei(medchemzhao@163.com) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Guo, Dong(guo@xzhmu.edu.cn) ; Liu, Tongchao(tongchao_liu@simm.ac.cn)
英文摘要Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC50 value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin-Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.
WOS关键词BOSUTINIB ; NEOPLASIA ; CANCER
资助项目National Natural Science Foundation of China ; Natural Science Foundation of Jiangsu Province ; Program for Innovative Research Team of the Ministry of Education ; Program for Liaoning Innovative Research Team in University ; [82173658] ; [81773572] ; [22077110] ; [BK20200106]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000888005000001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/304554]  
专题新药研究国家重点实验室
通讯作者Zhao, Dongmei; Zhou, Yubo; Guo, Dong; Liu, Tongchao
作者单位1.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou 221004, Jiangsu, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.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
Yang, Bowen,Zhang, Haoran,Li, Na,et al. Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:19.
APA Yang, Bowen.,Zhang, Haoran.,Li, Na.,Gao, Lixin.,Jiang, Hong.,...&Liu, Tongchao.(2022).Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.JOURNAL OF MEDICINAL CHEMISTRY,19.
MLA Yang, Bowen,et al."Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease".JOURNAL OF MEDICINAL CHEMISTRY (2022):19.

入库方式: OAI收割

来源:上海药物研究所

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