PO.MCB05.02 · 分子与细胞生物学
用于癌症治疗的新型Ku靶向DNA-PK抑制剂的开发
Development of novel Ku-targeted DNA-PK inhibitors for cancer therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
DNA依赖性蛋白激酶（DNA-PK）是一个经临床验证的癌症治疗靶点。它在通过非同源末端连接（NHEJ）修复DNA双链断裂（DSB）以及在更广泛的DNA损伤反应（DDR）信号通路中发挥着重要作用。鉴于其在维持基因组稳定性方面的关键作用，以及在许多癌症中的上调和过度激活，DNA-PK是一个有吸引力的治疗靶点，可用于单药治疗以及与放疗或其他DNA损伤化疗药物联合使用。现有的DNA-PK抑制剂靶向催化亚基（DNA-PKcs），但存在选择性差、药代动力学欠佳以及剂量限制性毒性等问题。为克服这些局限性，我们开发了一系列同类首创的小分子抑制剂，可阻断Ku70/80与DNA的结合，即DNA-PK激活的起始和必需步骤。我们基于结构的药物发现项目已开发出新型的、具有类药性的Ku抑制剂，它们结合于Ku界面内的独特口袋，阻断DNA接近并有效关闭DNA-PK活性。这种新颖的、不依赖ATP的机制阻止NHEJ复合物的组装，提供了增强的选择性、降低的脱靶毒性，以及一种强大的癌症治疗新策略。先导化合物在纳摩尔浓度下即可强效抑制DNA-PK催化活性，阻断Ku依赖性的DNA结合，并使癌细胞对电离辐射、依托泊苷和博来霉素敏感，同时不影响正常细胞。概念验证研究证实了其靶向机制、药效学结合，以及在非小细胞肺癌（NSCLC）异种移植模型中对IR诱导的抗肿瘤活性的增强。此外，一类以诱导DNA损伤作为其主要疗效机制的新兴且不断壮大的ADC在临床中日益受到欢迎。Ku抑制剂作为ADC的联合搭档具有强有力的机制依据，有可能克服耐药性并改善DNA损伤诱导型ADC的治疗指数。我们的结果显示，与ADC拓扑异构酶I抑制剂DXd联合使用时疗效显著增强，提示Ku抑制通过损害非同源末端连接并使肿瘤细胞对有效载荷介导的DNA损伤敏感，从而增强了DXd诱导的细胞毒性。这些结果支持进一步将Ku抑制剂开发为抗癌治疗药物。
查看英文原文 English abstract
The DNA-dependent protein kinase (DNA-PK) is a clinically validated target for cancer therapy. It plays essential roles in the repair of DNA double-strand breaks (DSBs) via non-homologous end joining (NHEJ), and in the broader DNA damage response (DDR) signaling pathway. Given its pivotal roles in maintaining genomic stability, and its upregulation and hyperactivation in many cancers, DNA-PK is an attractive therapeutic target for single agent therapy and in combination with radiation or other DNA damaging chemotherapeutics. Existing DNA-PK inhibitors target the catalytic subunit (DNA-PKcs) but have suffered from poor selectivity, suboptimal pharmacokinetics, and dose-limiting toxicity. To overcome these limitations, we have developed a first-in-class series of small-molecule inhibitors that block Ku70/80 binding to DNA, the initial and essential step of DNA-PK activation. Our structure-based drug discovery program has led to the development of novel, drug-like Ku inhibitors that bind to unique pockets within the Ku interface, blocking DNA access and effectively shutting down DNA-PK activity. This novel, ATP-independent mechanism prevents assembly of NHEJ complexes, offering enhanced selectivity, reduced off-target toxicity, and a powerful new strategy for cancer therapy. Lead compounds potently inhibit DNA-PK catalytic activity at nanomolar concentrations, block Ku-dependent DNA binding, and sensitize cancer cells to ionizing radiation, etoposide, and bleomycin while sparing normal cells. Proof-of-concept studies confirm on-target mechanism, pharmacodynamic engagement, and enhancement of IR-induced antitumor activity in non-small cell lung cancer (NSCLC) xenograft models. Additionally, newly emerging and growing class of ADCs that induce DNA damage as their primary efficacious mechanism have been increasingly popular in the clinic. Ku inhibitors have strong mechanistic rationale as combination partners for ADCs, with the potential to overcome resistance and improve the therapeutic index of DNA damage inducing ADCs. Our results show significant increased efficacy in combination with the ADC topoisomeraseI inhibitor, DXd, suggesting that Ku inhibition enhances DXd-induced cytotoxicity by impairing non-homologous end joining and sensitizing tumor cells to payload-mediated DNA damage. These results support the further development of Ku inhibitors as anticancer therapeutics.
利益披露 Disclosure
K. Pawelczak, None..
P. S. VanderVere-Carozza, None..
M. Casiano, None..
L. Dobrolecki, None.