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

• DOI: 10.1016/j.scib.2024.05.017
• Publication Date: 2024-05-18T04:21:40Z
• Authors: Lingping Kong; Fanlu Meng; Ping Zhou; Ruixin Ge; Xiaoshan Geng; Zhihao Yang; Guo Li; Linlin Zhang; Jing Wang; Jinfeng Ma; Cheng Dong; Jun Zhou; Sijin Wu; Diansheng Zhong; Songbo Xie
• Keywords: Aptamer; Hotspot (geology); Cancer Therapy

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