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,th...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–protea some-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.展开更多
基金supported by the National Natural Science Foundation of China(32270892,32070708,81702678,32200613,and 82272672)China Postdoctoral Science Foundation(2023M742622)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-061B).
文摘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–protea some-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.
