Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Rep. 2019 Mar 12;26(11):2916-2928.e13. doi: 10.1016/j.celrep.2019.02.047.
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.
染色质相关蛋白 WDR5 是癌症药物抑制的一个很有前途的靶点。药物研发的重点是阻断 WDR5 的“WIN 结构域”，这是一个明确的口袋，可被小分子抑制剂阻断。各种癌症环境被认为是 WIN 结构域抑制剂的靶点，但对 WDR5 靶基因的理解不足以及对 WIN 结构域抑制剂的主要作用的理解不足阻碍了它们的应用。在这里，通过发现有效的 WIN 结构域抑制剂，我们证明 WIN 结构域将 WDR5 连接到一小部分基因座的染色质上，包括核糖体蛋白基因的一个特定亚群。WIN 结构域抑制剂可迅速将 WDR5 从染色质上置换下来，并降低相关基因的表达，导致翻译抑制、核仁应激和 p53 诱导。我们的研究定义了 WDR5 与染色质结合的一种模式，并预测 WIN 结构域阻断可能对多种癌症类型有效。
