PDF(Pubmed)
Abstract：
The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the \'WIN\' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.
摘要：
染色质相关蛋白WD重复结构域5（WDR5）是癌症药物发现的有希望的靶标，大多数努力阻断蛋白质上的精氨酸结合腔，称为“胜利”位点，将WDR5连接到染色质。WIN位点抑制剂（WINi）在体外对多种癌细胞类型具有活性，其中最值得注意的是源自MLL重排（MLLr）白血病的那些。肽模拟物WINi最初被提议通过与造血干细胞扩增相关的基因的失调来抑制MLLr细胞。我们对小分子WINi的发现和审讯，然而,揭示了它们在MLLr细胞系中起作用以抑制核糖体蛋白基因（RPG）转录，诱导核仁应力，激活p53。因为没有专门针对RPG表达的抗癌策略的先例，我们采用综合的多组学方法来进一步研究WINi在人类MLLr癌细胞中的作用机制。我们证明WINi诱导核糖体存量的消耗，伴随着广泛而适度的翻译窒息和可变mRNA剪接的变化，使p53拮抗剂MDM4失活。我们还表明，WINi与包括venetoclax和BET-bromodomain抑制剂在内的药物具有协同作用。一起,这些研究强化了这样一个概念,即WINi是一种新型的核糖体导向抗癌疗法,并为支持其在MLLr白血病和其他恶性肿瘤中的临床应用提供了资源.
