2. Academic Validation
  3. Design, synthesis and evaluation of Nur77 modulators for lysosome dysfunction-driven therapy of gastric cancer

Design, synthesis and evaluation of Nur77 modulators for lysosome dysfunction-driven therapy of gastric cancer

  • Eur J Med Chem. 2026 Jul 5:311:118823. doi: 10.1016/j.ejmech.2026.118823.
Jiangang Huang 1,  Zile Zhang 1,  Kexuan Chen 1,  Yanyao Zhang 2,  Jingbo Qin 3,  Hongyu Hu 4
Affiliations

Affiliations

  • 1 Xingzhi College, Zhejiang Normal University, Lanxi, 321100, China.
  • 2 College of Chemistry and Materials Science, Zhejiang Normal University, Jinhua, 321004, China.
  • 3 Guangdong Provincial Engineering Research Center of Molecular Imaging and Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine Foundation of Guangdong Province, The Fifth Afffliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China. Electronic address: [email protected].
  • 4 Xingzhi College, Zhejiang Normal University, Lanxi, 321100, China. Electronic address: [email protected].
PMID: 41950651 DOI: 10.1016/j.ejmech.2026.118823
Abstract

Gastric Cancer remains a major cause of Cancer mortality, and long-term control is still limited by recurrence, metastasis, and therapy resistance, creating a clear need for small molecules that act through noncanonical mechanisms. Lysosomes have become an attractive target because loss of lysosomal competence can translate into cytoplasmic vacuolization, impaired autophagic turnover, and ultimately cell death. Nur77 is a stress-responsive nuclear receptor implicated in tumor biology, but whether it can be pharmacologically harnessed to drive lysosome-centered vulnerability in gastric Cancer has not been well established. Here, we designed and synthesized a series of 2-(6-(4-methoxyphenyl)-2-methylnicotinoyl)-N-substituted carboxamide/carbothioamide derivatives and identified compound 6K as the lead. 6K potently inhibited the growth of gastric Cancer cells while showing low cytotoxicity toward normal gastric epithelial cells. In both HGC-27 and AGS cells, 6K reduced viability and clonogenic survival and rapidly induced prominent cytoplasmic vacuolization. In HGC-27 cells, 6K further caused LC3-II and p62 accumulation, loss of Lyso-Tracker signal, and partial rescue of vacuolization and colony formation by bafilomycin A1. 6K also induced Apoptosis, supported by increased PARP cleavage, TUNEL positivity, and Annexin V/PI staining. Mechanistically, 6K directly bound the Nur77 ligand-binding domain, and Nur77 overexpression attenuated 6K-driven lysosomal perturbation and apoptotic signaling. In an HGC-27 xenograft model, 6K at 20 mg/kg significantly suppressed tumor growth without obvious histopathological injury to major organs. Collectively, these findings define 6K as a tractable Nur77 modulator that couples lysosomal dysfunction to apoptotic death in gastric Cancer, providing a lead scaffold for lysosome-directed Anticancer therapy.

Keywords

Apoptosis; Gastric cancer; Lysosomal dysfunction; Nicotinoyl semicarbazide; Nur77.

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