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

Abstract 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 (IC 50  = 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 (IC 50  = 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.