State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2020 May 14;63(9):4644-4654. doi: 10.1021/acs.jmedchem.9b02058. Epub 2020 Mar 19.
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.
内源性蛋白水平的可逆改变仍然是一个问题。在此，我们设计了光可切换的偶氮苯-蛋白酶体靶向嵌合体（Azo-PROTACs），通过在 E3 连接酶配体和目标蛋白之间包含偶氮苯部分。Azo-PROTACs 是一种光控小分子工具，可用于细胞内的蛋白敲低。光诱导的构象变化可以将活性状态切换为诱导蛋白降解活性，这种活性可以通过在完整细胞中暴露于光来进行反向控制。我们比较了不同构象和连接子长度的 Azo-PROTACs 的蛋白降解能力。使用针对髓性白血病 K562 细胞中的 BCR-ABL 融合和 ABL 蛋白具有最佳降解能力的稳定形式，我们表明 Azo-PROTAC 将小分子 PROTAC 的强效蛋白敲低和易于细胞摄取特性与可逆光切换性相结合，提供了一种基于光诱导的可逆开/关特性的有前途的化学敲低策略。
