Abstract：
The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics.
摘要：
染色质相关蛋白WDR5（WD重复结构域5）是MYC的必需辅因子和核糖体蛋白基因转录的保守调节因子。它也是抗癌药物发现的高调目标，具有针对实体和血液恶性肿瘤的拟议用途。我们以前已经发现了有效的基于二氢异喹啉酮的WDR5WIN位点抑制剂，在动物模型中具有证明的功效和安全性。在这项研究中,我们试图优化双环核，以发现一系列具有改善效力和物理化学性质的新型WDR5WIN位点抑制剂。我们确定了3,4-二氢苯并[f][1,4]氧氮杂-5（2H）-酮核心作为有效的WDR5抑制剂的替代支架。此外,我们使用X射线结构分析来设计部分饱和的双环P7单元。与我们同类最佳的基于二氢异喹啉酮的对应物相比，这些基于苯并恶嗪酮的抑制剂表现出增加的细胞效力和选择性以及有利的物理化学性质。这项研究为发现更先进的WDR5WIN位点抑制剂开辟了途径，并支持它们作为新型抗癌疗法的发展。
