Synthesis Optimizationand Evaluation of Novel SmallMolecules as Antagonists of WDR5-MLL Interaction

机译：综合优化小小说的创作与评价分子作为WDR5-MLL相互作用的拮抗剂

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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 (Kdis = 7 μM), leading to identification of more potent antagonist >47 (Kdis = 0.3 μM).

机译：WD40重复蛋白WDR5在维持MLL复合物的完整性并完全激活其甲基转移酶功能中起着关键作用。 MLL复合物是SET1甲基转移酶的类似于胸腔的家族，催化组蛋白3上的赖氨酸4的三甲基化，并且它们已广泛参与多种癌症。最近已提出通过小分子与WDR5和MLL亚基相互作用的拮抗作用是抑制MLL1配合物活性的实用方法，N-（2-（4-甲基哌嗪-1-基）-5-取代-苯基）苯甲酰胺是报道了这种相互作用的有效和选择性拮抗剂。在这里，我们描述了原型化合物> 2 （Kdis = 7μM）的蛋白晶体结构指导的优化，从而鉴定出更有效的拮抗剂> 47 （Kdis = 0.3μM）。

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期刊名称 ACS Medicinal Chemistry Letters
作者
Yuri Bolshan; §; Matthäus 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; *; §;
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年(卷),期 2013(4),3
年度 2013
页码 353–357
总页数 5
原文格式 PDF
正文语种
中图分类药物化学;
关键词
WDR5 MLL SET1 methyltransferase complex peptide binding site small molecule antagonists;

机译：WDR5;MLL;SET1甲基转移酶复合物;肽结合位点;小分子拮抗剂;

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机译：新型小分子作为WDR5-MLL相互作用的拮抗剂的合成，优化和评价
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5. Evaluating the Effects of Antagonistic Interactions on Pathogen Inhibition by Streptomyces Isolates from a Disease Suppressive Soil [D] . Pereyra, Matthew. 2021

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Synthesis Optimizationand Evaluation of Novel SmallMolecules as Antagonists of WDR5-MLL Interaction

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