Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening

doi:10.1039/c8ra10074h

	Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening
	Tao, Hongru 1,3; Wang, Jun 2,3; Lu, Wenchao 3,4; Zhang, Rukang 3,4; Xie, Yiqian 3; Liu, Yu-Chih 6; Liu, Rongfeng 6; Yue, Liyan 3; Chen, Kaixian 3,4,7; Jiang, Hualiang 3,4
刊名	RSC ADVANCES
	2019-02-11
卷号	9 期号:9 页码:4917-4924
ISSN号	2046-2069
DOI	10.1039/c8ra10074h
通讯作者	Zhang, Yuanyuan(zhangyy@simm.ac.cn) ; Xu, Xiaohui(xxhxxh@shu.edu.cn) ; Luo, Cheng(cluo@mail.shcnc.ac.cn)
英文摘要	The general control nonrepressed protein 5 (GCN5) is an important target for drug design and drug discovery largely owing to its pathogenic role in malignancies. Chemical probes that target GCN5 have been developed in recent decades, but their potencies are still unsatisfactory. In this study, through an in-house developed AlphaScreen-based high throughput screening platform, radioactive acetylation assays and 2D-similarity based analogue searching, we discovered DC_HG24-01 as the novel hGCN5 inhibitor with the IC50 value of 3.1 +/- 0.2 mu M. Further docking studies suggested that DC_HG24-01 could occupy the binding pocket of acetyl-CoA cofactor, which laid the foundation for the development of more potent hGCN5 inhibitors in the future. At the cellular level, DC_HG24-01 could retard cell proliferation and block the acetylation of H3K14 leading to cell apoptosis and cell cycle arrest at the G1 phase in MV4-11 cell lines. Taken together, the discovery of DC_HG24-01 may serve as a good starting point to accelerate the development of more potent hGCN5 inhibitors through further structural decoration and provide new insight into the pharmacological treatment of leukemia.
资助项目	National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81803554] ; China Postdoctoral Science Foundation[2017M621571] ; K. C. Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401]
WOS关键词	HISTONE ACETYLATION ; CHROMATIN-STRUCTURE ; ACETYLTRANSFERASES ; TRANSCRIPTION ; COMPLEXES ; TARGETS ; GROWTH ; CANCER ; H3
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000459183800032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290436]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Yuanyuan; Xu, Xiaohui; Luo, Cheng
作者单位	1.Shanghai Univ, Sch Life Sci, 99 Shangda Rd, Shanghai 200444, Peoples R China 2.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 3.Chinese Acad Sci, State Key Lab Drug Res, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 6.Shanghai ChemPartner Life Sci Co Ltd, Vitro Biol, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China 7.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式 GB/T 7714	Tao, Hongru,Wang, Jun,Lu, Wenchao,et al. Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening[J]. RSC ADVANCES,2019,9(9):4917-4924.
APA	Tao, Hongru.,Wang, Jun.,Lu, Wenchao.,Zhang, Rukang.,Xie, Yiqian.,...&Luo, Cheng.(2019).Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening.RSC ADVANCES,9(9),4917-4924.
MLA	Tao, Hongru,et al."Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening".RSC ADVANCES 9.9(2019):4917-4924.