期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 118, 期 -, 页码 1-8出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.04.032
关键词
Histone methyltransfreases; MLL1-WDR5 interaction; Small molecular inhibitors; Leukemia
资金
- National Natural Science Foundation of China [81230078, 81202463, 91129732]
- Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGQ201103]
- 863 program [2012AA020301]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2010ZX09401-401, 2009ZX09501-003, 2014ZX09507002-005-015]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20130096110002]
MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 mu M) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds. (C) 2016 Elsevier Masson SAS. All rights reserved.
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