期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 9, 页码 4644-4654出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b02058
关键词
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资金
- National Natural Science Foundation of China [81773581, 81773639, 81803363, 81930100]
- Natural Science Foundation of Jiangsu Province of China [BK20160746]
- Double First Class Innovation Team of China Pharmaceutical University [CPU2018GY02]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- China Postdoctoral Science Foundation [1600010006, 2018T110576]
- program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education
- Qing Lan Project of Jiangsu Province by CAST
- Young Elite Scientists Sponsorship Program by CAST
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.
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