Light-induced protein degradation with photo-caged PROTACs,Journal of the American Chemical Society

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Light-induced protein degradation with photo-caged PROTACs
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2019-09-30 , DOI: 10.1021/jacs.9b06422
Gang Xue ₁ , Kun Wang ₂ , Danli Zhou ₁ , Hanbing Zhong ₂ , Zhengying Pan ₁

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Induction of protein degradation is emerging as a powerful strategy to modulate protein functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used to degrade a range of diverse proteins in vitro and in vivo. Here we present a type of photo-caged PROTACs (pc-PROTACs) to induce degradation activity with light. Photo-removable blocking groups were added to a degrader of Brd4, and the resulting molecule pc-PROTAC1 showed potent degradation activity in live cells only after light irradiation. Furthermore, this molecule efficiently degraded Brd4 and induced expected phenotypic changes in zebrafish. Additionally, this approach was successfully applied to construct pc-PROTAC3 of BTK. Thus a general strategy to induce protein degradation with light was established to augment the chemists' toolbox to study disease-relevant protein targets.

中文翻译：

使用光笼式 PROTAC 进行光诱导的蛋白质降解

诱导蛋白质降解正在成为调节蛋白质功能和改变细胞信号通路的有力策略。蛋白水解靶向嵌合体 (PROTAC) 已被用于在体外和体内降解一系列不同的蛋白质。在这里，我们提出了一种光笼式 PROTACs (pc-PROTACs) 以诱导光降解活动。将光可去除的封闭基团添加到 Brd4 的降解剂中，所得分子 pc-PROTAC1 只有在光照射后才能在活细胞中显示出有效的降解活性。此外，该分子有效地降解了 Brd4 并诱导了斑马鱼的预期表型变化。此外，该方法已成功应用于构建 BTK 的 pc-PROTAC3。因此，建立了一种用光诱导蛋白质降解的一般策略，以增强化学家的

更新日期：2019-09-30

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