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![]() ![]() |
刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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出版日期 | 2022-11-17 |
页码 | 19 |
ISSN号 | 0022-2623 |
DOI | 10.1021/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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