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Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening

文献类型：期刊论文

作者Zhang, Dan2,4,5; Han, Jie2,5,6; Lu, Wenchao2,5,6; Lian, Fulin5,6; Wang, Jun5,7; Lu, Tian5,7; Tao, Hongru5,8; Xiao, Senhao5,9; Zhang, Fengcai3,5; Liu, Yu-Chih1
刊名BIOORGANIC CHEMISTRY
出版日期2019-05-01
卷号86页码:494-500
ISSN号0045-2068
关键词Lysine acetylation Bromodomain Virtual screening BPTF inhibitor
DOI10.1016/j.bioorg.2019.01.035
通讯作者Zhao, Chunshen() ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要Bromodomain PHD finger transcription factor (BPTF), a bromodomain-containing protein, plays a crucial role in the regulation of downstream gene expression through the specific recognition of lysine acetylation on bulk histones. The dysfunction of BPTF is closely involved with the development and progression of many human diseases, especially cancer. Therefore, BPTF bromodomain has become a promising drug target for epigenetic cancer therapy. However, unlike BET family inhibitors, few BPTF bromodomain inhibitors have been reported. In this study, by integrating docking-based virtual screening with biochemical analysis, we identified a novel selective BPTF bromodomain inhibitor DCB29 with the IC50 value of 13.2 +/- 1.6 mu M by homogenous timeresolved fluorescence resonance energy transfer (HTRF) assays. The binding between DCB29 and BPTF was confirmed by NMR and SPR. Molecular docking disclosed that DCB29 occupied the pocket of acetylated H4 peptide substrate and provided detailed SAR explanations for its derivatives. Collectively, DCB29 presented great potential as a powerful tool for BPTF-related biological research and further medicinal chemistry optimization.
WOS关键词DOSE-ESCALATION ; BET INHIBITORS ; DOCKING ; PROTEIN ; OTX015 ; PAINS
资助项目China Postdoctoral Science Foundation[2017M621571] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; K. C. Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号WOS:000464108100052
源URL[http://119.78.100.183/handle/2S10ELR8/289989]  
专题新药研究国家重点实验室
通讯作者Zhao, Chunshen; Luo, Cheng
作者单位1.Shanghai ChemPartner Co LTD, Zhangfiang Hitech Pk, Shanghai 201203, Peoples R China
2.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
3.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China
4.Guizhou Univ, Sch Pharmaceut Sci, Key Lab Guizhou Fermentat Engn & Biomed, Guizhou Engn Lab Synthet Drugs, Guiyang 550025, Guizhou, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
7.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, Nanjing 210023, Jiangsu, Peoples R China
8.Shanghai Univ, Sch Life Sci, 99 Shanghai Rd, Shanghai 200444, Peoples R China
9.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Dan,Han, Jie,Lu, Wenchao,et al. Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening[J]. BIOORGANIC CHEMISTRY,2019,86:494-500.
APA Zhang, Dan.,Han, Jie.,Lu, Wenchao.,Lian, Fulin.,Wang, Jun.,...&Luo, Cheng.(2019).Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening.BIOORGANIC CHEMISTRY,86,494-500.
MLA Zhang, Dan,et al."Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening".BIOORGANIC CHEMISTRY 86(2019):494-500.

入库方式： OAI收割

来源：上海药物研究所

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