PDF(Pubmed)
Abstract：
WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.
摘要：
WD重复结构域5（WDR5）是许多多蛋白复合物的核心支架组件，这些复合物在细胞核中执行各种关键的染色质中心过程。WDR5是混合谱系白血病MLL/SET复合物的组成部分，并将MYC定位于肿瘤关键靶基因的染色质。作为这些复合物的一部分，WDR5在维持多种人类癌症的肿瘤发生中起作用，这些癌症通常与不良预后有关。因此，WDR5已被认为是治疗实体肿瘤和血液肿瘤的有吸引力的治疗靶标。以前,WDR5-相互作用(WIN)位点的小分子抑制剂和WDR5降解剂在癌细胞系中显示出强大的体外细胞功效,并确立了WDR5的治疗潜力.然而,在动物疾病模型中,通过口服给药,这些药物在药理学相关剂量下未显示出显著的体内功效.我们已经发现WDR5WIN位点抑制剂,其通过基于结构的设计以双环杂芳基P7单元为特征,并且解决我们先前系列的小分子抑制剂的局限性。重要的是,我们的先导化合物表现出增强的目标效能，优异的口服药代动力学（PK）概况，以及通过口服给药在小鼠MV4:11皮下异种移植模型中的有效剂量依赖性体内功效。此外，这些体内探针在啮齿类动物的重复高剂量方案下显示出优异的耐受性,证明了WDR5WIN位点抑制机制的安全性.总的来说，我们的结果为WDR5WIN位点抑制剂用作潜在的抗癌治疗药物提供了有力支持.
