Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface
文献类型：期刊论文
| 作者 | Li, Lianchun1,2; Zhou, Ran2; Geng, Heji1; Yue, Liyan2; Ye, Fei3; Xie, Yiqian2; Liu, Jingqiu2; Kong, Xiangqian2; Jiang, Hualiang2 ; Huang, Jiandong1
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2014-05-01 |
| 卷号 | 24期号:9页码:2090-2093 |
| 关键词 | Menin Mixed lineage leukaemia Pharmacophore-based virtual screening Inhibitors |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2014.03.055 |
| 文献子类 | Article |
| 英文摘要 | Menin functions as an oncogenic cofactor of mixed lineage leukaemia (MLL) fusion proteins in leukaemogenesis. The menin-MLL interface is a potential therapeutic target in acute leukaemia cases. In this study, approximately 900 clinical compounds were evaluated and ranked using pharmacophore-based virtual screening, the top 29 hits were further evaluated by biochemical analysis to discover the inhibitors that target the menin-MLL interface. Two aminoglycoside antibiotics, neomycin and tobramycin, were identified as menin-MLL inhibitors with binding affinities of 18.8 and 59.9 mu M, respectively. The results of thermal shift assay validated the direct interactions between the two antibiotics and menin. The results of isothermal titration calorimetry showed that the equilibrium dissociation constant between menin and neomycin was approximately 15.6 mu M. We also predicted the binding modes of inhibitors at the menin-MLL interface through molecular docking analysis. The results indicated that neomycin and tobramycin competitively occupy the binding site of MLL. This study has shed light on the development of powerful probes and new therapies for MLL-mediated leukaemogenesis. (C) 2014 Elsevier Ltd. All rights reserved. |
| WOS关键词 | DRUG DISCOVERY ; MLL GENE ; PROTEIN ; TRANSFORMATION ; HOXA9 ; COMPLEXES ; DOCKING ; MEIS1 ; GLIDE |
| 资助项目 | Hi-Tech Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21210003] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program''[2013ZX09507-004] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program''[2013ZX09507001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program''[2014ZX09 507002-005-012] ; State Key Laboratory of Drug Research[SIMM1403KF-06] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000334337100011 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277106]  |
| 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 | Ye, Fei |
| 作者单位 | 1.Fuzhou Univ, Coll Chem & Chem Engn, Fuzhou 350002, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Beijing 100864, Peoples R China; 3.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Lianchun,Zhou, Ran,Geng, Heji,et al. Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2014,24(9):2090-2093. |
| APA | Li, Lianchun.,Zhou, Ran.,Geng, Heji.,Yue, Liyan.,Ye, Fei.,...&Luo, Cheng.(2014).Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,24(9),2090-2093. |
| MLA | Li, Lianchun,et al."Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 24.9(2014):2090-2093. |
入库方式： OAI收割
来源：上海药物研究所
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