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

Jiangang Huang¹, Zile Zhang¹, Kexuan Chen¹

¹Xingzhi College, Zhejiang Normal University, Lanxi, 321100, China.

European Journal of Medicinal Chemistry

|April 8, 2026

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.

Insights

A new compound, 6K, effectively targets gastric cancer cells by disrupting lysosomal function and inducing apoptosis. This novel therapeutic approach shows promise for treating gastric cancer, a leading cause of mortality.

Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

Gastric cancer poses a significant mortality risk, with limited long-term control due to recurrence, metastasis, and therapy resistance.
Lysosomes are emerging as therapeutic targets, as compromised lysosomal function can lead to cell death.
The role of the stress-responsive nuclear receptor Nur77 in gastric cancer and its potential as a drug target remain underexplored.

Purpose of the Study:

To design and synthesize novel small molecules targeting lysosomal function in gastric cancer.
To identify a lead compound that selectively inhibits gastric cancer cell growth by modulating Nur77.
To investigate the mechanism of action and in vivo efficacy of the lead compound.

Main Methods:

Synthesis and screening of 2-(6-(4-methoxyphenyl)-2-methylnicotinoyl)-N-substituted carboxamide/carbothioamide derivatives.
In vitro assessment of cell viability, clonogenic survival, and apoptosis in gastric cancer cell lines (HGC-27, AGS).
Analysis of lysosomal function markers (LC3-II, p62, Lyso-Tracker) and Nur77 interaction.
In vivo efficacy study using an HGC-27 xenograft mouse model.

Main Results:

Compound 6K demonstrated potent inhibition of gastric cancer cell growth with low cytotoxicity to normal cells.
6K induced significant cytoplasmic vacuolization, impaired autophagic turnover, and apoptosis in gastric cancer cells.
6K directly bound to the Nur77 ligand-binding domain, and its effects were attenuated by Nur77 overexpression.
In vivo, 6K significantly suppressed tumor growth in an HGC-27 xenograft model without major organ toxicity.

Conclusions:

Compound 6K is a potent Nur77 modulator that induces gastric cancer cell death via lysosomal dysfunction and apoptosis.
6K represents a promising lead scaffold for developing novel lysosome-directed anticancer therapies for gastric cancer.
Targeting lysosomal pathways through Nur77 modulation offers a new strategy for overcoming gastric cancer resistance.

Read full analysis

Keywords:

Apoptosis Gastric cancer Lysosomal dysfunction Nicotinoyl semicarbazide Nur77

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