2. Academic Validation
  3. Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77

Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77

  • Bioorg Chem. 2023 Nov:140:106795. doi: 10.1016/j.bioorg.2023.106795.
Hongyu Hu 1,  Gang Lin 2,  Fengming He 2,  Jie Liu 2,  Rong Jia 3,  Kun Li 2,  Wenbin Hong 4,  Meijuan Fang 5,  Jin-Zhang Zeng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China; Xingzhi College, Zhejiang Normal University, Lanxi 321004, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 3 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China.
  • 5 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: [email protected].
PMID: 37657195 DOI: 10.1016/j.bioorg.2023.106795
Abstract

Hepatic fibrosis remains a great challenge clinically. The Orphan Nuclear Receptor Nur77 is recently suggested as the critical regulator of transforming growth factor-β (TGF-β) signaling, which plays a central role in multi-organic fibrosis. Herein, we optimized our previously reported Nur77-targeted compound 9 h for attempting to develop effective and safe anti-hepatic fibrosis agents. The critical pharmacophore scaffold of pyridine-carbonyl-hydrazine-1-carboxamide was retained, while the naphthalene ring was replaced with an aromatic ring containing pyridyl or indole groups. Four series of derivatives were thus generated, among which the compound 16f had excellent binding activity toward Nur77-LBD (KD = 470 nM) with the best inhibitory activity against the TGF- β 1 activation of hepatic stellate cells (HSCs) and low cytotoxicity to normal mice liver AML-12 cells (IC50 > 80 μM). In mice, 16f displayed potent activity against CCl4-induced liver fibrosis with improved liver function. Mechanistically, 16f-mediated inactivation of HSC and suppression of liver fibrosis were associated with its enhancement of autophagic flux in a Nur77-dependent manner. Together, 16f was identified as a potential anti-liver fibrosis agent. Our study suggests that Nur77 may serve as a critical anti-hepatic fibrosis target.

Keywords

Autophagy flux; Hepatic stellate cell; Hydrazine-1-carboxamide derivatives; Liver fibrosis; Nur77.

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