The Exploration of Indole-Based LSD1-Targeted Inhibitors for Enhanced Immune Response in Gastric Cancer via the PD-L1/PD-1 Axis

  • J Med Chem. 2025 May 8;68(9):9260-9278. doi: 10.1021/acs.jmedchem.4c02851.
Hang Zhang  1 ,  Yujie Zhang  1 ,  Yinping Geng  1 ,  Xuanlong Zhen  1 ,  Xiaodi Wang  1 ,  Qiange Yin  1 ,  Peng Zhang  1 ,  Yuanyuan Li  1 ,  Mengzhen Zhang  1 ,  Yi-Chao Zheng  1 ,  Bing-Rui Liu  2 ,  Hui-Min Liu  1 ,  Hai-Wei Xu  1
Affiliations
  • 1. Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 2. School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China.
PMID: 40257403 DOI: 10.1021/acs.jmedchem.4c02851
Abstract

Gastric Cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric Cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric Cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric Cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric Cancer.

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