自动RapTAC:一个多功能和可持续的平台,用于自动化快速合成和评估 PROTAC
Jiexuan Chen1, Mingfei Wu1, Jun Mo1
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Journal of medicinal chemistry
|January 4, 2025
概括
一个名为Auto-RapTAC的新平台,通过自动化和点击化学,简化了针对蛋白解的仿真体 (PROTACs) 的发现. 这使得能够快速识别和高通量选用于治疗开发的新型PROTACs.
科学领域:
- 药物发现 药物发现 药物发现
- 化学生物学 化学生物学
- 分子生物学分子生物学
背景情况:
- 发现新型蛋白质分解向嵌合体 (PROTACs) 在合成和生物评估吞吐量方面面临挑战.
- 有效识别PROTAC的化合物对于推进向蛋白质降解疗法至关重要.
研究的目的:
- 开发一个平台,用于快速,高吞吐量生成和选PROTACs.
- 为了克服传统的PROTAC发现方法的局限性.
主要方法:
- 实验室自动化与点击化学和用于自主 PROTAC 合成的模块化构建块库的集成.
- 开发一种准备选 (R4S) 方法,利用基于光的测试来评估高通量降解活性.
- 该平台的应用用于识别针对CDK2,CDK12和BCL6.6的新型PROTACs.
主要成果:
- 成功地自主生成了多种PROTACs,具有多种链接器和E3结合酶连接体.
- 对 PROTAC 降解活动的高效高通量评估.
- 在每个目标的8天时间内,确定了6种新的针对CDK2,CDK12和BCL6的PROTACs.
结论:
- 自动RapTAC平台显著加速了PROTAC的发现和开发.
- 这种自动化方法可以快速识别各种治疗点的强效PROTACs.
- 该平台具有广泛应用的潜力,用于发现新的PROTAC和其他异位生物功能模式.
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