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

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

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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 exten-sive efforts,the absence of a druggable active site for small molecules has rendered these mutants ther-apeutically 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 expo-nential 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 suc-cessfully developed a selective p53-R175H degrader,named dp53m.dp53m induces the ubiquitin-protea some-dependent degradation of p53-R175H while sparing wildtype p53.Importantly,dp53m demon-strates significant antitumor efficacy in p53-R1 75H-driven cancer cells both in vitro and in vivo,without toxicity.Moreover,dp53m significantly and synergistically improves the sensitivity of these cells to cis-platin,a commonly used chemotherapy drug.These findings provide evidence of the potential therapeu-tic value of dp53m in p53-R175H-driven cancers.

P53AptamerPROTACCancerDrug resistance

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

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Department of Medical Oncology,Tianjin Medical University General Hospital,Tianjin 300052,China

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

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

Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment,Lung Cancer Institute,Tianjin Medical University General Hospital,Tianjin 300052,China

Haihe Laboratory of Cell Ecosystem,State Key Laboratory of Medicinal Chemical Biology,College of Life Sciences,Nankai University,Tianjin 300071,China

Wisdom Lake Academy of Pharmacy,Xi'an Jiaotong-Liverpool University,Suzhou 215028,China

Department of Ophthalmology,Tianjin Medical University General Hospital,Laboratory of Molecular Ophthalmology,Tianjin Key Laboratory of Ocular Trauma,Tianjin Medical University,Tianjin 300052,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationTianjin Key Medical Discipline(Specialty)Construction Project

32270892320707088170267832200613822726722023M742622TJYXZDXK-061B

2024

10.1016/j.scib.2024.05.017

科学通报(英文版)
中国科学院

科学通报(英文版)

CSTPCD
ISSN：1001-6538
年,卷(期)：2024.69(13)