化学
喹唑啉
泛素
癌症研究
细胞毒性T细胞
泛素连接酶
DNA损伤
药理学
体外
生物化学
DNA
立体化学
生物
基因
作者
Fu-Cheng Wang,Bin Peng,Ting-Ting Ren,Shao-Peng Liu,Jing-Rui Du,Zi-Hao Chen,Tingting Zhang,Xi Gu,Mo Li,Sheng‐Li Cao,Xingzhi Xu
标识
DOI:10.1021/acs.jmedchem.2c00432
摘要
Quinazoline and its derivatives have drawn much attention in the development of potential antitumor agents. Here, we synthesized a series of 1,2,3-triazole derivatives of quinazoline at the C6 position and evaluated for their cytotoxic activity in various human cancer cell lines. We found that compound 5a was the most cytotoxic to HCT-116 cells (IC50, 0.36 μM). Target profiling found that 5a directly binds to both the autophagy-associated protein SQSTM1/P62 and the E3 ligase RNF168, promoting their interaction. Consistently, 5a treatment induces a decrease in RNF168-mediated H2A ubiquitination and compromises homologous recombination-mediated DNA repair, thus increasing the sensitivity of HCT-116 to X-ray radiation. Moreover, 5a suppressed xenografted tumor growth in mice in a dose-dependent manner. Taken together, the 1,2,3-triazole derivative of quinazoline 5a may serve as a novel compound for tumor therapy based on its role in promoting a P62/RNF168 interaction.
科研通智能强力驱动
Strongly Powered by AbleSci AI