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 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.
基金项目
National Natural Science Foundation of China(32270892)
National Natural Science Foundation of China(32070708)
National Natural Science Foundation of China(81702678)
National Natural Science Foundation of China(32200613)
National Natural Science Foundation of China(82272672)
China Postdoctoral Science Foundation(2023M742622)
Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-061B)
NETL
NSTL
万方数据