Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1.,ACS Medicinal Chemistry Letters

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Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-11-25 , DOI: 10.1021/acsmedchemlett.9b00460
Xiaomin Ni _{1,

2} , David Heidenreich _{1,

2} , Thomas Christott ₃ , James Bennett ₃ , Moses Moustakim ₃ , Paul E Brennan _{1,

2,

3} , Oleg Fedorov ₃ , Stefan Knapp _{1,

2} , Apirat Chaikuad _{1,

2}

Affiliation

YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.

中文翻译：

MLLT1中替代哌嗪-脲YEATS域结合剂相互作用机理的结构性见解。

包含YEATS结构域的MLLT1是一个乙酰基/酰基赖氨酸阅读器结构域，其结构与研究透彻的溴结构域不同，并且与癌症的发展密切相关。在这里，我们将哌嗪-脲衍生物表征为MLLT1的乙酰基/酰基赖氨酸模拟部分。与最近描述的基于苯并咪唑-酰胺的抑制剂相比，晶体结构揭示了该化学型的独特相互作用机制，从而利用了蛋白质内的不同结合口袋。因此，哌嗪-脲支架为靶向YEATS域家族提供了另一种策略。

更新日期：2019-12-03

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