2. Academic Validation
  3. Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators

Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators

  • Eur J Med Chem. 2020 Oct 15;204:112608. doi: 10.1016/j.ejmech.2020.112608.
Baicun Li 1,  Jie Yao 2,  Kaiqiang Guo 2,  Fengming He 2,  Kun Chen 2,  Zongxin Lin 2,  Shunzhi Liu 2,  Jiangang Huang 2,  Qiaoqiong Wu 2,  Meijuan Fang 3,  Jinzhang Zeng 4,  Zhen Wu 5
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China; State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: [email protected].
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: [email protected].
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: [email protected].
PMID: 32717483 DOI: 10.1016/j.ejmech.2020.112608
Abstract

Nur77 is a potential target for the treatment of Cancer such as HCC. Herein, we detailed the discovery of a novel series of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as potential Nur77 modulators. The studies of antiproliferative activity and Nur77-binding affinity of target compounds resulted in the discovery of a lead candidate (10g), which was a good Nur77 binder (KD = 3.58 ± 0.16 μM) with a broad-spectrum antiproliferative activity against all tested hepatoma cells (IC50 < 2.0 μM) and was low toxic to normal LO2 cells. 10g could up-regulate Nur77 expression and mediate sub-cellular localization of Nur77 to induce Apoptosis in hepatocellular carcinoma cell lines, which relied on 10g inducing Nur77-dependent Autophagy and endoplasmic reticulum stress as the upstream of Apoptosis. Moreover, the in vivo assays verified that 10g significantly inhibited xenograft tumor growth. These results indicate that 10g has the potential to be developed as a novel Nur77-targeting anti-hepatoma drug.

Keywords

Antitumor; Autophagy; ER stress; Indole; Nur77; Quinoline.

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