Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction

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• 作者：Yuri Bolshan ; Matth盲us Getlik ; Ekaterina Kuznetsova ; Gregory A. Wasney ; Taraneh Hajian ; Gennadiy Poda ; Kong T. Nguyen ; Hong Wu ; Ludmila Dombrovski ; Aiping Dong ; Guillermo Senisterra ; Matthieu Schapira ; Cheryl H. Arrowsmith ; Peter J. Brown ; Rima Al-awar ; Masoud Vedadi ; David Smil
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：4
• 期：3
• 页码：353-357
• 全文大小：291K
• 年卷期：v.4,no.3(March 14, 2013)
• ISSN：1948-5875

文摘

The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K_dis = 7 渭M), leading to identification of more potent antagonist 47 (K_dis = 0.3 渭M).

Keywords:

WDR5; MLL; SET1 methyltransferase complex; peptide binding site; small molecule antagonists