Discovery of 1,8-acridinedione derivatives as novel GCN5 inhibitors via high throughput screening

doi:10.1016/j.ejmech.2018.02.005

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	Discovery of 1,8-acridinedione derivatives as novel GCN5 inhibitors via high throughput screening
	Xiong, Huan 1,6; Han, Jie 2; Wang, Jun 2,3; Lu, Wenchao 2,4; Wang, Chen 2,4; Chen, Yu 2,4; Lian, Fulin 2; Zhang, Naixia2 ; Liu, Yu-Chih 5; Zhang, Chenhua 5
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-05-10
卷号	151 页码:740-751
关键词	Epigenetics Histone acetyltransferase GCN5 High throughput screening 1,8-Acridinedione derivative
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.02.005
文献子类	Article
英文摘要	The general control nonrepressed protein 5 (GCN5) plays a crucial role in many biological processes. Dysregulation of GCN5 has been closely related to various human diseases, especially cancers. Hence, the exploitation of small molecules targeting GCN5 is essential for drug design and academic research. Based on the amplified luminescent proximity homogeneous assay screen methodology, we performed high throughput screening and discovered a novel GCN5 inhibitor DC_G16 with 1,8-acridinedione scaffold. Structure optimization led to the identification of a highly potent inhibitor, namely DC_G16-11 with the half-maximal inhibitory concentration (IC50) value of 6.8 mu M. The binding between DC_G16-11 and GCN5 was demonstrated by NMR and SPR with a K-D of 4.2 mu M. It could also inhibit proliferation and induce cell cycle arrest and apoptosis in cancer cells while it presented minimal effects on normal cells. Herein, DC_G16-11 could be applied as a validated chemical probe for GCN5-related biological function research and presented great potential for clinical disease treatment. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81430084] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020361]
WOS关键词	HISTONE ACETYLTRANSFERASE GCN5 ; SMALL-MOLECULE INHIBITOR ; GLUCOSE-METABOLISM ; CHEMICAL BIOLOGY ; ACETYLATION ; TRANSCRIPTION ; P300 ; PCAF ; H3 ; PGC-1-ALPHA
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:000432640900050
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279762]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Lu, Wencong; Luo, Cheng; Zhou, Bing
作者单位	1.Shanghai Univ, Dept Chem, Coll Sci, 99 Shangda Rd, Shanghai 200444, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China; 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China; 5.Shanghai ChemPartner Life Sci Co Ltd, In Vitro Biol, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xiong, Huan,Han, Jie,Wang, Jun,et al. Discovery of 1,8-acridinedione derivatives as novel GCN5 inhibitors via high throughput screening[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,151:740-751.
APA	Xiong, Huan.,Han, Jie.,Wang, Jun.,Lu, Wenchao.,Wang, Chen.,...&Zhou, Bing.(2018).Discovery of 1,8-acridinedione derivatives as novel GCN5 inhibitors via high throughput screening.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,151,740-751.
MLA	Xiong, Huan,et al."Discovery of 1,8-acridinedione derivatives as novel GCN5 inhibitors via high throughput screening".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 151(2018):740-751.