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Updated: Jun 25, 2025

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一个基于DNA吸收体的工程 PROTAC,用于精确治疗p53-R175H热点突变驱动的癌症

Lingping Kong¹, Fanlu Meng¹, Ping Zhou²

¹Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin 300052, China.

Science bulletin

|May 29, 2024

概括

研究人员开发了一种新型的化向化明体 (PROTAC),用于降解致癌的p53-R175H突变蛋白. 这种向性癌症治疗显示出显著的抗瘤疗效,并增强化疗反应.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

突变的p53蛋白质在癌症中经常过度表达,具有瘤性功能获取活动.
在突变的p53中缺乏可用药物的活性部位,阻碍了基于小分子的癌症疗法.
向突变的p53是一种有前途的策略,用于开发新的癌症治疗方法.

研究的目的:

开发一种选择性蛋白质分解向化体 (PROTAC),向常见的p53-R175H突变体.
使用一种新的计算方法,为p53-R175H设计一种高亲和度DNA吸收体.
在临床前癌症模型中评估开发的PROTAC的治疗潜力.

主要方法:

一种新的代分子对接指导后SELEX方法被用来设计一个DNA的aptamer.
在 PROTAC 分子 (dp53m) 的理性设计中,阿普塔默被用作结合剂组件.
在实验室和体内使用携带p53-R175H突变的癌细胞评估dp53m的疗效和选择性.

主要成果:

成功开发了一种选择性p53-R175H降解剂dp53m,它针对突变蛋白进行ubiquitin-proteasome降解.
dp53m在p53-R175H驱动的癌细胞中显示出显著的抗瘤活性,没有可观察到的毒性.
同时使用dp53m与思丁协同增强了癌细胞对化疗的敏感性.

结论:

开发的PROTAC,dp53m,为由p53-R175H突变驱动的癌症提供了一个有前途的治疗策略.
通过PROTACs针对突变p53的向降解是克服治疗耐药性的可行方法.
dp53m显示了组合疗法的潜力,以改善特定癌症类型的治疗结果.

关键词:

亚普特美尔 (Aptamer) 是一种药物.癌症癌症癌症癌症药物耐药性药物耐药性药物耐药性在P53中,P53是P53 这就是PROTAC.

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