2. Academic Validation
  3. Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells

Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells

  • J Med Chem. 2023 Mar 23;66(6):3896-3916. doi: 10.1021/acs.jmedchem.2c01593.
Xing-Jie Dai 1,  Li-Juan Zhao 1 2,  Long-Hua Yang 1,  Ting Guo 1,  Lei-Peng Xue 1,  Hong-Mei Ren 1,  Zhi-Li Yin 1,  Xiao-Peng Xiong 1,  Ying Zhou 1,  Shi-Kun Ji 1,  Hui-Min Liu 1,  Hong-Min Liu 1,  Ying Liu 3,  Yi-Chao Zheng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.
  • 2 State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.
  • 3 Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China.
PMID: 36856685 DOI: 10.1021/acs.jmedchem.2c01593
Abstract

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for Cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 μM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric Cancer.

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