结构导向设计和优化共价VHL向化硫化PROTACs的结构导向设计和优化
Rishi R Shah1,2, Elena De Vita2,3, Preethi S Sathyamurthi1
1GSK, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.
Journal of medicinal chemistry
|March 13, 2024
概括
研究人员开发了用于向蛋白质降解 (TPD) 的新型共价Von Hippel-Lindau (VHL) 配体. 这些配体使得能够设计出强大的蛋白质分解向嵌合体 (PROTACs),用于降解各种蛋白质,扩大治疗选择.
科学领域:
- 药用化学 医学化学
- 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:
- 化向的仿真体 (PROTACs) 是用于向蛋白质降解 (TPD) 的异质生物功能分子.
- 性PROTACs具有优势,但设计它们具有广泛的感兴趣蛋白 (POI) 范围是具有挑战性的.
- 希佩尔-林道 (VHL) E3结合酶是PROTAC开发的常见目标.
研究的目的:
- 为 PROTAC 应用设计和优化新的共价 VHL 配体.
- 为了证明这些共价联结体在双功能降解剂中的实用性.
- 为了扩大共价E3结合酶的基质范围,PROTACs.
主要方法:
- 基于硫尼尔化物VHL配体的结构导向设计.
- 在HIF1α结合位点内,VHL在Ser110的共价变异.
- 将连接物纳入双功能降解剂,用于向蛋白质降解.
主要成果:
- 成功设计和优化共价VHL配体.
- 使用开发的PROTACs证明了BRD4和雄激素受体的向蛋白质降解.
- 建立了第一个共价VHL配体,用于直接用于双功能降解器设计.
结论:
- 新型共价VHL配体在PROTAC设计中是有效的.
- 这项工作扩大了共价E3结合酶PROTACs的适用性.
- 这些发现为开发向蛋白质降解剂提供了新的策略.
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