天津医科大学Songbo Xie，天津医科大学总医院Diansheng Zhong，西安交通大学Sijin Wu等人合作，近期取得重要工作进展。他们研究提出了基于工程化DNA适配体的PROTAC策略，这一策略可特异性治疗p53-R175H突变驱动的癌症。相关研究成果2024年5月18日在线发表于《科学通报》杂志上。

据介绍，靶向致癌突变p53是癌症治疗的一种有吸引力的策略，因为在各种癌症类型中，p53功能获得突变和异位表达的频率很高。尽管进行了广泛的努力，但由于缺乏小分子的可药用活性位点，这些突变体在治疗上是不可行的。

研究人员开发了一种针对p53-R175H的选择性和有效的蛋白水解靶向嵌合体（PROTAC），这是一种具有显性阴性和致癌活性的常见热点突变体。使用一种新的迭代分子对接引导的后SELEX（通过指数富集进行配体的系统演化）方法，研究团队合理地设计了一种对p53-R175H具有改进的亲和力和特异性的高性能DNA适体。

利用由此产生的适体作为PROTAC的粘合剂，研究人员成功地开发了一种选择性p53-R175H降解剂，命名为dp53m。dp53m诱导p53-R175H的泛素-蛋白酶体依赖性降解，同时保留野生型p53。重要的是，dp53m在体外和体内对p53-R175H驱动的癌症细胞显示出显著的抗肿瘤功效，且没有毒性。

此外，dp53m显著且协同提高了这些细胞对常用化疗药物顺铂的敏感性。这些发现为dp53m在p53-R175H驱动癌症中的潜在治疗价值提供了证据。

附：英文原文

Title: An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

Author: Sijin Wu f, Diansheng Zhong a, Songbo Xie g

Issue&Volume: 2024/05/18

Abstract: Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully develop a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin-proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo, without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

DOI: 10.1016/j.scib.2024.05.017

Source: https://www.sciencedirect.com/science/article/pii/S2095927324003517