Epigenetic regulatory complexes including WDR5, EZH2, PRMT5, NO66 and UTX control transcription of the Runx2 gene during osteoblast differentiation
MOLECULAR BIOLOGY OF THE CELL
Authors: Rojas, A. P.; Allende, M.; Montecino, M.; Van Zundert, B.
Abstract
Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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
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 (IC50 = 0.3 mu M) 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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