期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 56, 期 9, 页码 1847-1855出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.6b00185
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资金
- National Key Research & Development Plan [2016YF1201003]
- National Basic Research Program [2015CB910304]
- Hi-Tech Research and Development Program of China [2014AA01A302]
- National Natural Science Foundation of China [21210003, 81230076, 81430084]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12050201]
- Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]
Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 +/- 0.12 mu M and a K-D of 14.70 +/- 2.13 mu M, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI(50) values of 0.84 mu M and 0.54 mu M, respectively.
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