Light-Induced Protein Degradation with Photocaged PROTACs

被引：241

作者：

Xue, Gang ^{[1
]}

Wang, Kun ^{[2
]}

Zhou, Danli ^{[1
]}

Zhong, Hanbing ^{[2
]}

Pan, Zhengying ^{[1
]}

机构：

[1] Peking Univ, State Key Lab Chem Oncogen, Engn Lab Chiral Drug Synth, Sch Chem Biol & Biotechnol,Shenzhen Grad Sch, Shenzhen 518055, Guangdong, Peoples R China

[2] Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Guangdong, Peoples R China

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2019年 / 141卷 / 46期

基金：

中国国家自然科学基金;

关键词：

E3 UBIQUITIN LIGASE; ZEBRAFISH; CEREBLON; COMPLEX; SYSTEM;

D O I：

10.1021/jacs.9b06422

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：18370 / 18374

页数：5

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