Discovery of 1,3,5-triazine-based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer

Abstract

Lysine-specific demethylase 1 (LSD1), the first identified histone lysine-specific demethylase, plays a crucial role in mediating immune responses in gastric cancer. Most LSD1 inhibitors undergoing clinical trials are irreversible, which has driven significant interest in developing structurally diverse reversible inhibitors. In this study, we present a potent 1,3,5-triazine-based LSD1 inhibitor, XP-2, discovered through high-throughput screening (HTS) of our in-house compound library and subsequent structure-activity relationship (SAR) studies, exhibiting a half maximal inhibitory concentration (IC50) of 0.116 μmol/L. XP-2 enhanced the susceptibility of gastric cancer cells to T cell-mediated cytotoxicity by downregulating programmed cell death ligand 1 (PD-L1) expression, thereby disrupting the programmed cell death protein 1 (PD-1)/PD-L1 interaction. Furthermore, XP-2 significantly inhibited the proliferation of gastric cancer cells without inducing notable toxicity. Pharmacokinetic evaluation revealed favorable oral exposure and a moderate half-life in mice. In conclusion, this study provided a promising LSD1 inhibitor with a novel scaffold and promising pharmacokinetic properties, supporting its further development as an immunomodulator for gastric cancer treatment.