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The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening

文献类型：期刊论文

作者Ye, Xiaoqing1; Zhang, Rukang2; Lian, Fulin2; Zhang, Weiyao1; Lu, Wenchao2; Han, Jie2; Zhang, Naixia2; Jin, Jia1; Luo, Cheng2; Chen, Kaixian2,4,5
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2019-02-15
卷号29期号:4页码:638-645
关键词WDR5-MLL1 interaction Leukemia Small-molecule High-throughput screening Fluorescence polarization (FP)
ISSN号0960-894X
DOI10.1016/j.bmcl.2018.12.035
通讯作者Ye, Fei(yefei@zstu.edu.cn) ; Ding, Hong(hding@simm.ac.cn)
英文摘要The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It's urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities in vitro against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC50 values of 9.63 +/- 1.46 mu M. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5.
WOS关键词H3K4 METHYLTRANSFERASE ACTIVITY ; LEUKEMIA MLL PROTEIN ; HIGH-AFFINITY ; WDR5 ; OPTIMIZATION ; DISRUPTION ; MECHANISMS
资助项目Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; Natural Science Foundation of Zhejiang Province[LY18H300008] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81803339] ; Chinese Academy of Science[XDA12020353] ; K. C. Wong Education Foundation
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000457262100023
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/290533]  
专题新药研究国家重点实验室
通讯作者Ye, Fei; Ding, Hong
作者单位1.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr,State Key Lab Drug Re, Shanghai 201203, Peoples R China
3.China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Jiangsu, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式
GB/T 7714		 Ye, Xiaoqing,Zhang, Rukang,Lian, Fulin,et al. The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2019,29(4):638-645.
APA Ye, Xiaoqing.,Zhang, Rukang.,Lian, Fulin.,Zhang, Weiyao.,Lu, Wenchao.,...&Ding, Hong.(2019).The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,29(4),638-645.
MLA Ye, Xiaoqing,et al."The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 29.4(2019):638-645.

入库方式： OAI收割

来源：上海药物研究所

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