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

doi:10.1016/j.bioorg.2019.01.035

	Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening
	Zhang, Dan 1,2,9; Han, Jie 2,3,9; Lu, Wenchao 2,3,9; Lian, Fulin 2,3; Wang, Jun 2,4; Lu, Tian 2,4; Tao, Hongru 2,5; Xiao, Senhao2,7 ; Zhang, Fengcai 2,8; Liu, Yu-Chih 6; Liu, Rongfeng 6; Zhang, Naixia 2,3; Jiang, Hualiang2,3,7,9 ; Chen, Kaixian2,3,7,9 ; Zhao, Chunshen 1; Luo, Cheng 2,3,7,9
	2019-05
发表期刊	BIOORGANIC CHEMISTRY (IF:4.5[JCR-2023],4.7[5-Year])
ISSN	0045-2068
卷号	86 页码:494-500
发表状态	已发表
DOI	10.1016/j.bioorg.2019.01.035
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.
关键词	Lysine acetylation Bromodomain Virtual screening BPTF inhibitor
收录类别	SCI ; SCIE
语种	英语
资助项目	Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401]
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Organic
WOS记录号	WOS:000464108100052
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS关键词	DOSE-ESCALATION ; BET INHIBITORS ; DOCKING ; PROTEIN ; OTX015 ; PAINS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/34263
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_陈凯先组免疫化学研究所_特聘教授组_蒋华良组
通讯作者	Zhao, Chunshen; Luo, Cheng
作者单位	1.Guizhou Univ, Sch Pharmaceut Sci, Key Lab Guizhou Fermentat Engn & Biomed, Guizhou Engn Lab Synthet Drugs, Guiyang 550025, Guizhou, Peoples R China 2.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 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, Nanjing 210023, Jiangsu, Peoples R China 5.Shanghai Univ, Sch Life Sci, 99 Shanghai Rd, Shanghai 200444, Peoples R China 6.Shanghai ChemPartner Co LTD, Zhangfiang Hitech Pk, Shanghai 201203, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 8.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China 9.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
通讯作者单位	生命科学与技术学院
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.