PDF(Pubmed)
Abstract：
WDR5 is a conserved nuclear protein that scaffolds the assembly of epigenetic regulatory complexes and moonlights in functions ranging from recruiting MYC oncoproteins to chromatin to facilitating the integrity of mitosis. It is also a high-value target for anti-cancer therapies, with small molecule WDR5 inhibitors and degraders undergoing extensive preclinical assessment. WDR5 inhibitors were originally conceived as epigenetic modulators, proposed to inhibit cancer cells by reversing oncogenic patterns of histone H3 lysine 4 methylation-a notion that persists to this day. This premise, however, does not withstand contemporary inspection and establishes expectations for the mechanisms and utility of WDR5 inhibitors that can likely never be met. Here, we highlight salient misconceptions regarding WDR5 inhibitors as epigenetic modulators and provide a unified model for their action as a ribosome-directed anti-cancer therapy that helps focus understanding of when and how the tumor-inhibiting properties of these agents can best be understood and exploited.
摘要：
WDR5是一种保守的核蛋白，可支持表观遗传调节复合物和月光的组装，其功能范围从招募MYC癌蛋白到染色质，以促进有丝分裂的完整性。它也是抗癌治疗的高价值目标，与小分子WDR5抑制剂和降解物进行广泛的临床前评估。WDR5抑制剂最初被认为是表观遗传调节剂，提出通过逆转组蛋白H3赖氨酸4甲基化的致癌模式来抑制癌细胞-这一观点一直持续到今天。这个前提,然而,无法承受当代检查，并建立了可能永远无法满足的WDR5抑制剂的机制和效用的期望。这里,我们强调了关于WDR5抑制剂作为表观遗传调节剂的显著误解,并为它们作为核糖体导向的抗癌治疗提供了一个统一的模型,这有助于集中了解何时以及如何最好地理解和利用这些药物的肿瘤抑制特性.
