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通过SuFEx反应构建PROTAC分子,以诱导p300/CBP蛋白质降解

Qiuyu Guo¹, Chunxia Yang², Xuyuan Liu²

¹Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.

Bioorganic & medicinal chemistry

|April 23, 2025

概括

研究人员开发了一种使用点击化学的新方法,以创建用于蛋白质降解的蛋白质分解向化马 (PROTACs). 这一策略有效地建立了PROTAC库,以研究链接长度对蛋白质降解的影响.

科学领域:

药用化学医学化学
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

对链接器长度的结构-活性关系 (SAR) 研究对于优化蛋白解-向金马 (PROTACs) 是至关重要的.
已建立的PROTAC合成化学存在,但需要新的方法来有效地构建和探索图书馆.
PROTACs是诱导向蛋白质降解的异构生物功能分子.

研究的目的:

引入一种新的点击化学方法,使用硫交换 (SuFEx) 反应来快速合成PROTAC库.
研究不同链接长度对新合成的PROTACs蛋白质降解效能的影响.
为了探索SuFEx在构建用于向蛋白质降解的PROTACs中的应用,点击化学.

主要方法:

使用SuFEx反应,一种点击化学类型,合成了一个小的PROTAC库.
合成涉及硫尼尔化物前体 (与p300/CBP连接体,CPI644相关) 与不同氨基碳链长度的Cereblon (CRBN) 连接体的amidation.
生成的PROTACs的蛋白质降解活性在一个过度表达MDA-MB-468的p300/CBP细胞系中进行了评估.

主要成果:

SuFEx的点击化学策略使得能够高效地构建一个具有不同链接长度的 PROTAC 库.
合成的PROTACs显示了蛋白质降解效应,验证了SuFEx方法的实用性.
这种方法为SAR研究生成PROTAC提供了一个快速的途径,特别是关于链接器优化.

结论:

SuFEx反应为快速合成 PROTAC 库提供了一个多功能和高效的平台.
这种点击化学方法有助于在PROTAC设计中探索向蛋白质降解的链接长度SAR.
开发的战略有助于加速发现和优化基于PROTAC的新型治疗方法.

关键词:

这就是PROTAC.蛋白质降解蛋白质降解 SuFEx SuFEx 是一个 p300/CBP/CBP 公司

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