放射治疗触发的蛋白质溶解以向瘤中的奇米拉前药物激活
Chunrong Yang1, Yuchen Yang1, Yujie Li2
1Department of Chemistry, Center for Bioanalytical Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China.
Journal of the American Chemical Society
|December 21, 2022
概括
放射治疗触发的PROTAC前药物 (RT-PROTACs) 可以精确控制蛋白质降解,最大限度地降低全身毒性. 这种新的方法使用X射线激活PROTACs进行向治疗.
科学领域:
- 生物化学
- 分子生物学
- 癌症学
背景情况:
- 针对蛋白质溶解的基因组 (PROTACs) 有效降解蛋白质,包括先前
- 没有药物
- 但组织外降解的系统性毒性是令人担忧的.
研究的目的:
- 开发放射治疗触发的PROTAC前药物 (RT-PROTAC) 用于空间时间控制蛋白质降解.
- 在临床前癌症模型中研究RT- PROTAC的疗效和安全性.
主要方法:
- 将X射线可诱导的酸嵌入到基向的PROTAC中,以创建第一个RT-PROTAC.
- 通过X射线激活RT- PROTAC的体外和体内评估.
- 在MCF-7异种移植模型中评估BRD4和BRD2降解和协同抗瘤效应.
主要成果:
- 在被X射线激活之前,RT-PROTAC前药的活性很小.
- 激活的RT- PROTAC有效降解了BRD4和BRD2,类似于常规的PROTAC.
- 在与放射治疗相结合时,RT- PROTAC显示出协同作用的抗瘤作用.
结论:
- 放射治疗触发的激活可以精确地控制PROTAC介导的蛋白质降解.
- RT- PROTAC 是一个有希望的策略来缓解与 PROTAC 治疗相关的全身毒性.
- 这种方法通过将PROTAC与放射治疗相结合,为向癌症治疗提供了新的途径.
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