1. The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening.
- Author
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Ye, Xiaoqing, Zhang, Rukang, Lian, Fulin, Zhang, Weiyao, Lu, Wenchao, Han, Jie, Zhang, Naixia, Jin, Jia, Luo, Cheng, Chen, Kaixian, Ye, Fei, and Ding, Hong
- Subjects
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SMALL molecules , *PROTEIN-protein interactions , *LEUKEMIA treatment , *FLUORESCENCE polarization immunoassay , *HIGH throughput screening (Drug development) - Abstract
Graphical abstract Abstract The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It's urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities in vitro against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC 50 values of 9.63 ± 1.46 µM. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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