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

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.