Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay

doi:10.1038/aps.2017.188

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	Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay
	Lu, Tian 2; Hu, Jun-chi 1,5; Lu, Wen-chao 1,5; Han, Jie 1,5; Ding, Hong1 ; Jiang, Hao 1,5; Zhang, Yuan-yuan 1; Yue, Li-yan 1; Chen, Shi-jie 1; Jiang, Hua-liang1,3,4
刊名	ACTA PHARMACOLOGICA SINICA
	2018-09
卷号	39 期号:9 页码:1544-1552
关键词	AlphaScreen high-throughput screening SMARCA2 bromodomain small molecule inhibitor
ISSN号	1671-4083
DOI	10.1038/aps.2017.188
文献子类	Article
英文摘要	SMARCA2 is a critical catalytic subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes. Dysregulation of SMARCA2 is associated with several diseases, including some cancers. SMARCA2 is multi-domain protein containing a bromodomain (BRD) that specifically recognizes acetylated lysine residues in histone tails, thus playing an important role in chromatin remodeling. Many potent and specific inhibitors targeting other BRDs have recently been discovered and have been widely used for cancer treatments and biological research. However, hit discovery targeting SMARCA2-BRD is particularly lacking. To date, there is a paucity of reported high-throughput screening (HTS) assays targeting the SMARCA2-BRD interface. In this study, we developed an AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors and optimized the physicochemical conditions including pH, salt concentrations and detergent levels. Through an established AlphaScreen-based high-throughput screening assay against an in-house compound library, DCSMO6 was identified as a novel SMARCA2-BRD inhibitor with an IC50 value of 39.9 +/- 3.0 mu mol/L. Surface plasmon resonance demonstrated the binding between SMARCA2-BRD and DCSMO6 (K-d =38.6 mu mol/L). A similarity-based analog search led to identification of DCSM06-05 with an IC50 value of 9.0 +/- 1.4 mu mol/L. Molecular docking was performed to predict the binding mode of DCSM06-05 and to decipher the structural basis of the influence of chemical modifications on inhibitor potency. DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMARCA2-related functional studies.
资助项目	Ministry of Science and Technology of China[2017YFB0202600] ; Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084]
WOS关键词	STATISTICAL PARAMETER ; CANCER-THERAPY ; DISCOVERY ; COMPLEXES ; TRANSCRIPTION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000442758500014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279601]
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
通讯作者	Chen, Kai-xian; Chai, Hui-fang; Luo, Cheng
作者单位	1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Guiyang Univ Tradit Chinese Med, Dept Pharm, Guiyang 550025, Guizhou, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Materia Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Lu, Tian,Hu, Jun-chi,Lu, Wen-chao,et al. Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay[J]. ACTA PHARMACOLOGICA SINICA,2018,39(9):1544-1552.
APA	Lu, Tian.,Hu, Jun-chi.,Lu, Wen-chao.,Han, Jie.,Ding, Hong.,...&Luo, Cheng.(2018).Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay.ACTA PHARMACOLOGICA SINICA,39(9),1544-1552.
MLA	Lu, Tian,et al."Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay".ACTA PHARMACOLOGICA SINICA 39.9(2018):1544-1552.