Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening

doi:10.1016/j.bmc.2021.116054

	Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening
	Sun, Yanli 1,2; Lu, Haibo 2,4; Fang, Xueyu2,3 ; Xiao, Senhao2,3 ; Yang, Feng 2,4; Chen, Yantao 2; Wang, Hongbo 1; Li, Xiaopeng 1; Lu, Jing 1; Lin, Hua 2; Luo, Cheng 2,4; Zhao, Kehao 1; Chen, Shijie 2
	2021-03-15
发表期刊	BIOORGANIC & MEDICINAL CHEMISTRY (IF:3.3[JCR-2023],3.1[5-Year])
ISSN	0968-0896
EISSN	1464-3391
卷号	34 页码:#VALUE!
DOI	10.1016/j.bmc.2021.116054
摘要	Tumor suppressor p53-binding protein 1 (53BP1), a tantem tudor domain (TTD) protein, takes part in DNA Damage Repair (DDR) pathways through the specific recognition of lysine methylation on histones. The dysregulation of 53BP1 is closely related to the development of many diseases including cancer. Moreover, recent studies found that deficiency of 53BP1 could increase the efficiency of precise CRISPR/Cas9 genome editing. Thus, discovery of inhibitor is beneficial to the study of biological functions of 53BP1 and the application of CRISPR/Cas9 genome editing. UNC2170 and its derivatives have been reported as 53BP1 targeted small molecular inhibitors with modest activities. Hence, to discover better 53BP1 inhibitors, we conducted an AlphaScreen assay based high-throughput screening (HTS) and identified a novel and effective 53BP1-TTD inhibitor DP308 which disrupts the binding between 53BP1 and H4K20me2 peptide with an IC50 value of 1.69 +/- 0.73 mu M. Both Microscale Themophoresis (MST) and Surface Plasmon Resonance (SPR) assays confirmed the direct binding between DP308 and 53BP1-TTD protein with binding affinity (K-d) of about 2.7 mu M. Molecular docking studies further suggested that DP308 possibly occupies the H4K20me2 binding pocket of the 53BP1-TTD aromatic cage. These results demonstrated that DP308 is a promising small molecule inhibitor for further optimization towards a more potent chemical probe of 53BP1. Additionally, it could be a potential valuable tool for applying to gene editing therapy by increasing the efficiency of CRISPR/Cas9 genome editing.
关键词	53BP1-TTD H4K2Ome2 AlphaScreen HTS Novel inhibitor
收录类别	SCI ; SCIE
语种	英语
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
WOS记录号	WOS:000620805700003
出版者	PERGAMON-ELSEVIER SCIENCE LTD
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/125736
专题	生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Zhao, Kehao; Chen, Shijie
作者单位	1.Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm, Yantai 264005, Peoples R China; 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China; 4.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Sun, Yanli,Lu, Haibo,Fang, Xueyu,et al. Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2021,34:#VALUE!.
APA	Sun, Yanli.,Lu, Haibo.,Fang, Xueyu.,Xiao, Senhao.,Yang, Feng.,...&Chen, Shijie.(2021).Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening.BIOORGANIC & MEDICINAL CHEMISTRY,34,#VALUE!.
MLA	Sun, Yanli,et al."Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening".BIOORGANIC & MEDICINAL CHEMISTRY 34(2021):#VALUE!.