1. High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity.
- Author
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Li, Dong-Dong, Chen, Wei-Lin, Wang, Zhi-Hui, Xie, Yi-Yue, Xu, Xiao-Li, Jiang, Zheng-Yu, Zhang, Xiao-Jin, You, Qi-Dong, and Guo, Xiao-Ke
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HISTONE methyltransferases , *LEUKEMIA , *PROTEIN-protein interactions , *GENE expression , *APOPTOSIS - Abstract
MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 ( DDO-2084 ) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 ( DDO-2117 , IC 50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC 50 = 0.19 μM) in HMT assay. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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