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Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity

文献类型：期刊论文

作者Wang, Jubo1; Li, Tinghan1; Zhao, Tengteng1; Wu, Tizhi1; Liu, Chuang3; Ding, Hong2; Li, Zhiyu1; Bian, Jinlei1,2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-09-15
卷号178页码:782-801
关键词Wogonin CDK9 AML Flavonoid Antitumor
ISSN号0223-5234
DOI10.1016/j.ejmech.2019.06.024
通讯作者Li, Zhiyu(zhiyuli@cpu.edu.cn) ; Bian, Jinlei(bianjl@cpu.edu.cn)
英文摘要Wogonin, a natural product isolated from the plant Scutellaria baicalensis, has been shown to be a potent and selective inhibitor of CDK9. With the purpose of investigating the activity and selectivity of this chemical scaffold, several series of wogonin derivatives were prepared and screened for CDK9 inhibition and cellular antiproliferative activity. Among these compounds, the drug-like compound 51 showed potent activity against CDK9 (IC50 = 19.9 nM) and MV4-11 cell growth (IC50 = 20 nM). In addition, compound 51 showed much improved physicochemical properties, such as water solubility, compared with the parent compound wogonin. The follow-up studies showed that the compound 51 is selective toward CDK9-overexpressing cancer cells over normal cells. Preliminary mechanism studies on the anticancer effect indicated that 51 inhibited the proliferation of MV4-11 cells via caspase-dependent apoptosis. In addition, highlighted compound 51 showed significant antitumor activity in mouse acute myeloid leukemia (AML) models without producing apparent toxic effects in vivo, which gave us a new tool for further investigation of CDK9-targeted inhibitor as a potential antitumor drug especially for AML. (C) 2019 Elsevier Masson SAS. All rights reserved.
WOS关键词DERIVATIVES ; SUFFICIENT ; BAICALEIN ; DRIVE
资助项目National Natural Science Foundation of China[81703347] ; National Natural Science Foundation of China[21672260] ; National Natural Science Foundation of China[21372260] ; National Natural Science Foundation of Jiangsu Province of China[BK20170743] ; National Natural Science Foundation of Jiangsu Province of China[BK20171393] ; Double First-class University Project[CPU2018GY07] ; State Key Laboratory of Drug Research[SIMM1903KF-03]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000480664100056
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/288988]  
专题新药研究国家重点实验室
通讯作者Li, Zhiyu; Bian, Jinlei
作者单位1.China Pharmaceut Univ, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 211198, Jiangsu, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
3.China Pharmaceut Univ, Dept Biochem, Nanjing 211198, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jubo,Li, Tinghan,Zhao, Tengteng,et al. Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,178:782-801.
APA Wang, Jubo.,Li, Tinghan.,Zhao, Tengteng.,Wu, Tizhi.,Liu, Chuang.,...&Bian, Jinlei.(2019).Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,178,782-801.
MLA Wang, Jubo,et al."Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 178(2019):782-801.

入库方式： OAI收割

来源：上海药物研究所

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