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  3. The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening

The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening

  • Bioorg Med Chem Lett. 2019 Feb 15;29(4):638-645. doi: 10.1016/j.bmcl.2018.12.035.
Xiaoqing Ye 1,  Rukang Zhang 2,  Fulin Lian 2,  Weiyao Zhang 1,  Wenchao Lu 2,  Jie Han 2,  Naixia Zhang 2,  Jia Jin 1,  Cheng Luo 2,  Kaixian Chen 3,  Fei Ye 4,  Hong Ding 5
Affiliations

Affiliations

  • 1 College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
  • 2 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China.
  • 4 College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China. Electronic address: yefei@zstu.edu.cn.
  • 5 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: hding@simm.ac.cn.
PMID: 30626558 DOI: 10.1016/j.bmcl.2018.12.035
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 IC50 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.

Keywords

Fluorescence polarization (FP); High-throughput screening; Leukemia; Small-molecule; WDR5-MLL1 interaction.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148817
    WDR5-MLL1抑制剂
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