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

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.