Discovery of a Nur77-mediated cytoplasmic vacuolation and paraptosis inducer (4-PQBH) for the treatment of hepatocellular carcinoma

  • Bioorg Chem. 2022 Apr;121:105651. doi: 10.1016/j.bioorg.2022.105651.
Baicun Li  1 ,  Jiangang Huang  2 ,  Jie Liu  2 ,  Fengming He  2 ,  Fangfang Wen  2 ,  Changming Yang  2 ,  Wang Wang  3 ,  Tong Wu  2 ,  Taige Zhao  2 ,  Jie Yao  4 ,  Shunzhi Liu  2 ,  Yingkun Qiu  2 ,  Meijuan Fang  5 ,  Jinzhang Zeng  6 ,  Zhen Wu  7
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; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China; Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing 100029, 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. Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China; College of Bioscience and Bioengineering, Jiangxi Agricultural University, Nanchang 330045, China.
  • 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; Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610000, China.
  • 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].
  • 6. 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].
  • 7. 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: 35182885 DOI: 10.1016/j.bioorg.2022.105651
Abstract

Nur77, an Orphan Nuclear Receptor, has antitumor activity in hepatocellular carcinoma (HCC). However, its antitumor mechanisms of action in HCC are complicated and rarely reported. Our recent work demonstrated that certain quinoline-Schiff-base derivatives were good Nur77 mediators that exerted excellent anti-HCC activities in vitro and in vivo. Interestingly, these compounds shared similar chemical structures, but they displayed different Nur77-targeted Anticancer mechanisms of action. As a continuous work, we synthesized a series of 4-(quinoline-4-amino) benzoylhydrazide derivatives and evaluated their anti-HCC activity and binding affinity to Nur77 in vitro. Compound 4-PQBH emerged as the best Nur77 binder (KD = 1.17 μM) and has potentially selective cytotoxicity to HCC cells. Mechanistically, 4-PQBH extensively induced caspase-independent cytoplasmic vacuolization and Paraptosis through Nur77-mediated ER stress and Autophagy. Moreover, 4-PQBH exhibited an effective xenograft tumor inhibition by modulating Nur77-dependent cytoplasmic vacuolation and Paraptosis. This paper is the first to disclose that chemotherapeutic agents targeting Nur77-mediated cytoplasmic vacuolization and Paraptosis may provide a promising strategy to combat HCC that frequently evade the Apoptosis program.

Keywords
4-(Quinoline-4-amino) Benzoylhydrazide; Cytoplasmic vacuolation; Hepatocellular Carcinoma; Nur77; Paraptosis.
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