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

Lingping Kong¹, Fanlu Meng¹, Ping Zhou², Ruixin Ge², Xiaoshan Geng², Zhihao Yang³, Guo Li¹, Linlin Zhang¹, Jing Wang⁴, Jinfeng Ma⁴, Cheng Dong³, Jun Zhou⁵, Sijin Wu⁶, Diansheng Zhong⁷, Songbo Xie⁸

Affiliations

¹ Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin 300052, China.
² Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China.
³ The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁴ Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
⁵ Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China; Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
⁶ Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou 215028, China. Electronic address: sijin_wu@foxmail.com.
⁷ Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: dzhong@tmu.edu.cn.
⁸ Department of Ophthalmology, Tianjin Medical University General Hospital, Laboratory of Molecular Ophthalmology, Tianjin Key Laboratory of Ocular Trauma, Tianjin Medical University, Tianjin 300052, China. Electronic address: songboxie@tmu.edu.cn.

PMID: 38811338
DOI: 10.1016/j.scib.2024.05.017

Free article

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 developed 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.

Keywords: Aptamer; Cancer; Drug resistance; P53; PROTAC.

Sci Bull (Beijing) . 2024 Jul 15;69(13):2122-2135. doi: 10.1016/j.scib.2024.05.017. Epub 2024 May 18. (IF:18.800).

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

Abstract

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