Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface.
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 μM, 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 μM. 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.
College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Lianchun
L
Li
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Ran
R
Zhou
College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, China.
Heji
H
Geng
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Liyan
L
Yue
Zhejiang Sci-Tech University, College of Life Sciences, Hangzhou, China. Electronic address: yefei@zstu.edu.cn.
Fei
F
Ye
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Yiqian
Y
Xie
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Jingqiu
J
Liu
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Xiangqian
X
Kong
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Hualiang
H
Jiang
College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, China.
Jiandong
J
Huang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China. Electronic address: cluo@simm.ac.cn.
Cheng
C
Luo
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009355:Neomycin / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014031:Tobramycin / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D009355:Neomycin; D014031:Tobramycin
Inhibitors; Menin; Mixed lineage leukaemia; Pharmacophore-based virtual screening