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

文献类型：期刊论文

作者Sun, Yanli1,2; Lu, Haibo2,4; Fang, Xueyu2,3; Xiao, Senhao2,3; Yang, Feng2,4; Chen, Yantao2; Wang, Hongbo1; Li, Xiaopeng1; Lu, Jing1; Lin, Hua2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2021-03-15
卷号34页码:116054
ISSN号0968-0896
关键词53BP1-TTD H4K2Ome2 AlphaScreen HTS Novel inhibitor
DOI10.1016/j.bmc.2021.116054
文献子类Article
英文摘要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.
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:000620805700003
源URL[http://119.78.100.183/handle/2S10ELR8/309396]  
专题新药研究国家重点实验室
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,2021,34:116054.
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,34,116054.
MLA Sun, Yanli,et al."Discovery of a novel 53BP1 inhibitor through AlphaScreen-based high-throughput screening".BIOORGANIC & MEDICINAL CHEMISTRY 34(2021):116054.

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来源：上海药物研究所

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