Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
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DOI：
10.1016/j.celrep.2019.02.047
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发表时间：
2019-03-12
期刊：
影响因子：
8.8
通讯作者：
Tansey, William P.
中科院分区：
文献类型：
--
作者：
Aho, Erin R.;Wang, Jing;Tansey, William P.
染色质相关蛋白WDR 5是一个有前途的药物抑制癌症的目标。药物发现的努力集中在阻断WDR 5的“WIN位点”上，WDR 5是一个明确的口袋，适合小分子抑制。已经提出了各种癌症背景作为WIN位点抑制剂的靶标，但是缺乏对WDR 5靶基因和WIN位点抑制剂的主要作用的理解阻碍了它们的效用。在这里，通过发现有效的WIN位点抑制剂，我们证明了WIN位点将WDR 5连接到一小群位点的染色质，包括核糖体蛋白基因的特定子集。WIN位点抑制剂迅速从染色质中置换WDR 5并降低相关基因的表达，引起翻译抑制、核仁应激和p53诱导。我们的研究定义了WDR5与染色质结合的模式，并预测WIN位点阻断可能对多种癌症类型具有效用。
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.