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.

组蛋白赖氨酸特异性去甲基化酶1（Histone lysine specific demethylase 1，LSD1）已被确认为癌症治疗的重要表观靶点。尽管已有多款LSD1抑制剂进入临床试验，但开发新型强效LSD1抑制剂仍是一项亟待突破的挑战。本研究将抗精神病药物氯丙嗪鉴定为LSD1抑制剂（半最大抑制浓度IC50 = 5.135 μM），并合成了一系列氯丙嗪衍生物。其中，化合物3s（IC50 = 0.247 μM）的活性最为强劲。更为关键的是，化合物3s可在细胞层面抑制LSD1，并在BGC-823与MFC细胞中下调程序性死亡配体1（programmed cell death-ligand 1，PD-L1）的表达，从而增强T细胞杀伤应答。体内实验证实，化合物3s可在免疫健全小鼠体内抑制MFC细胞增殖，且未引发显著毒性。综上，本研究结果表明，这款带有吩噻嗪骨架的新型LSD1抑制剂3s可作为先导化合物，用于进一步开发以激活胃癌患者的T细胞免疫应答。