2. Academic Validation
  3. A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

  • J Med Chem. 2022 Nov 4. doi: 10.1021/acs.jmedchem.2c00432.
Fu-Cheng Wang 1 2,  Bin Peng 1,  Ting-Ting Ren 3,  Shao-Peng Liu 3,  Jing-Rui Du 3,  Zi-Hao Chen 3,  Ting-Ting Zhang 3,  Xiaoyang Gu 4,  Mo Li 4,  Sheng-Li Cao 3,  Xingzhi Xu 1
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, PR China.
  • 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518060, PR China.
  • 3 Department of Chemistry, Capital Normal University, Beijing, 100048, PR China.
  • 4 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 10091, PR China.
PMID: 36331508 DOI: 10.1021/acs.jmedchem.2c00432
Abstract

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.

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