Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Dong Dong Li, Wei Lin Chen, Xiao Li Xu, Fen Jiang, Lei Wang, Yi Yue Xie, Xiao Jin Zhang, Xiao Ke Guo, Qi Dong You, Hao Peng Sun

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31 Citations (Scopus)


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 μM) 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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 8 Aug 2016
Externally publishedYes


  • Histone methyltransfreases
  • Leukemia
  • MLL1-WDR5 interaction
  • Small molecular inhibitors

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