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

被引:52
作者
Bolshan, Yuri [1 ]
Getlik, Matthaeus [2 ]
Kuznetsova, Ekaterina [1 ]
Wasney, Gregory A. [1 ]
Hajian, Taraneh [1 ]
Poda, Gennadiy [2 ]
Nguyen, Kong T. [1 ]
Wu, Hong [1 ]
Dombrovski, Ludmila [1 ]
Dong, Aiping [1 ]
Senisterra, Guillermo [1 ]
Schapira, Matthieu [1 ]
Arrowsmith, Cheryl H. [1 ]
Brown, Peter J. [1 ]
Al-awar, Rima [2 ]
Vedadi, Masoud [1 ]
Smil, David [1 ]
机构
[1] Univ Toronto, Struct Genom Consortium, MaRS Ctr, Toronto, ON M5G 1L7, Canada
[2] Ontario Inst Canc Res, MaRS Ctr, Toronto, ON M5G 0A3, Canada
基金
英国惠康基金;
关键词
WDR5; MLL; SET1 methyltransferase complex; peptide binding site; small molecule antagonists; HISTONE H3; DROSOPHILA-TRITHORAX; ACUTE LEUKEMIAS; CORE COMPLEX; HOX GENES; MLL; METHYLATION; RECOGNITION; METHYLTRANSFERASES; TRANSLOCATIONS;
D O I
10.1021/ml300467n
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The WD40-repeat protein WDRS 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 mu M), leading to identification of more potent antagonist 47 (K-dis = 0.3 mu M).
引用
收藏
页码:353 / 357
页数:5
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