通过目标激活实现的生物直角PROTAC前药物
Mengyang Chang1, Feng Gao2, Devin Pontigon1
1Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Journal of the American Chemical Society
|June 16, 2023
概括
这项研究引入了点击释放的PROTACs (crPROTACs),这是一种新型前药策略,可选择性地激活蛋白质分解,向癌细胞中的嵌合体,最大限度地降低毒性并实现向蛋白质降解.
科学领域:
- 生物化学
- 分子生物学
- 化学生物学
背景情况:
- 化向基因组 (PROTACs) 具有治疗潜力,但由于非向蛋白降解而面临毒性问题.
- 制定精确控制PROTAC活动的策略对于最小化副作用至关重要.
- 通过癌症生物标志物激活的前体药物正在探索以提高PROTAC的选择性.
研究的目的:
- 开发一种针对癌细胞的PROTAC激活的生物对等,按需的前药物策略.
- 在癌细胞中创造一种选择性蛋白质降解系统,
- 研究点击释放PROTAC (crPROTAC) 方法的有效性.
主要方法:
- 设计的无活性PROTAC前药物 (TCO-ARV-771,TCO-DT2216) 通过将转环 (TCO) 与VHL E3无酸连接体结合.
- 使用素 (Tz) 修饰的RGD (c(RGDyK) -Tz) 针对癌细胞的整合蛋白αvβ3生物标志物进行前药激活.
- 使用生物直角点击释放机制进行选择性PROTAC激活和随后的蛋白质降解.
主要成果:
- 选择性激活PROTAC前药物是依赖于整体蛋白αβ3的.
- 激活的PROTACs有效地降解了癌细胞内的感兴趣蛋白质 (POI).
- 在不同于非癌细胞的癌细胞中证明了POI的向降解.
结论:
- 通过crPROTAC的策略,可以在目标上激活PROTAC,从而在癌细胞中选择性降解蛋白质.
- 这种生物对等方法提供了一种通过ubiquitin-proteasome途径诱导癌细胞死亡的潜在方法.
- crPROTAC是一种有希望的非生物策略,用于向癌症治疗,并减少非向效应.
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