2. Academic Validation
  3. Design, synthesis, and evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as anti-HCC agents targeting Nur77

Design, synthesis, and evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as anti-HCC agents targeting Nur77

  • Bioorg Chem. 2025 Oct 18:167:109113. doi: 10.1016/j.bioorg.2025.109113.
Shengwei Hu 1,  Xiaodan Li 1,  Mingyue Yu 2,  Haofan Zhang 1,  Xiang Wang 2,  Chen Qi 1,  Shiyan Huang 1,  Ziyi Xu 3,  Hongyu Hu 4,  Siming Chen 5,  Meijuan Fang 6,  Jinzhang Zeng 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
  • 2 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China.
  • 3 Intensive Care Unit, Xiang'an Hospital of Xiamen University, Xiamen 361102, China.
  • 4 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Shenzhen Research Institute of Xiamen University, Shenzhen, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: [email protected].
PMID: 41223584 DOI: 10.1016/j.bioorg.2025.109113
Abstract

Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited treatment options for advanced-stage patients. The Orphan Nuclear Receptor Nur77 has emerged as a promising therapeutic target in HCC. Leveraging a molecular hybridization strategy based on our previously reported Nur77 modulators (10g, 4-PQBH, and 8b), we have designed and synthesized three series of 1H-indole-2-carbohydrazide derivatives with the potential to act anti-HCC agents. Of these compounds, 12b exhibited potent anti-proliferative activity against HCC cell lines (HepG2, IC₅₀ = 0.51 ± 0.12 μM; HCCLM3, IC₅₀ = 2.07 ± 0.51 μM) and demonstrated a higher affinity for binding to Nur77 (KDFTA = 0.42 μM) than the positive control compound CSN-B (KDFTA= 0.78 μM). Mechanistic studies revealed that 12b stabilizes Nur77 by inhibiting its ubiquitin-proteasomal degradation, leading to Nur77-dependent Apoptosis via the ASK1-JNK/p38 pathway. Significantly, 12b suppressed tumor growth in HCCLM3 xenograft models without causing any observable toxicity, highlighting its therapeutic potential. These findings validate Nur77 as a viable target and establish 12b as a promising anti-HCC agent for further development.

Keywords

1H-Indole-2-carbohydrazide; ASK1-JNK/P38; Apoptosis; Hepatocellular carcinoma; Nur77.

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