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

doi:10.1016/j.ejmech.2019.06.024

	Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity
	Wang, Jubo 1; Li, Tinghan 1; Zhao, Tengteng 1; Wu, Tizhi 1; Liu, Chuang 3; Ding, Hong 2; Li, Zhiyu 1; Bian, Jinlei 1,2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2019-09-15
卷号	178 页码:782-801
关键词	Wogonin CDK9 AML Flavonoid Antitumor
ISSN号	0223-5234
DOI	10.1016/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.
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关键词	DERIVATIVES ; SUFFICIENT ; BAICALEIN ; DRIVE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000480664100056
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288988]
专题	中国科学院上海药物研究所
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.