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

• Published in: European journal of medicinal chemistry 2016-08, Vol.118, p.1-8
• Main Authors: Li, Dong-Dong, Chen, Wei-Lin, Xu, Xiao-Li, Jiang, Fen, Wang, Lei, Xie, Yi-Yue, Zhang, Xiao-Jin, Guo, Xiao-Ke, You, Qi-Dong, Sun, Hao-Peng
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Chemistry Techniques, Synthetic; Drug Design; Histone methyltransfreases; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - metabolism; Humans; Inhibitory Concentration 50; Leukemia; MLL1-WDR5 interaction; Molecular Docking Simulation; Myeloid-Lymphoid Leukemia Protein - metabolism; Protein Binding - drug effects; Protein Conformation; Small molecular inhibitors; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.04.032

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. [Display omitted] •A series of MLL1-WDR5 PPI small molecular inhibitors were designed and synthesized based on a co-crystal structure.•SAR of this series of compounds was discussed along with docking study.•Compound 23 was the most potent compound disturbing the interaction of MLL1-WDR5 with IC50 value 104 nM in FP assay.