Discovery of\n2‑Aryl-4-aminoquinazolin-Based\nLSD1 Inhibitors to Activate Immune Response in Gastric Cancer

LSD1\n(histone lysine-specific demethylase 1) has been gradually\ndisclosed to act as an immunomodulator to enhance antitumor immune\nresponse. Despite the identification of numerous potent LSD1 inhibitors,\nthere remains a lack of LSD1 inhibitors approved for marketing. Novel\nLSD1 inhibitors with different mechanisms are therefore needed. Herein,\nwe reported a series of novel quinazoline-based LSD1 inhibitors. Among\nthem, compound Z-1 exhibited the best LSD1 inhibitory activity (IC<sub>50</sub> = 0.108 μM). Z-1 also acted as a selective and cellular\nactive as an LSD1 inhibitor. Furthermore, Z-1 promoted response of\ngastric cancer cells to T-cell killing effect by decreasing PD-L1\nexpression and further attenuated the PD-1/PD-L1 interaction. In vivo,\nZ-1 exhibited significant suppression effect on the growth of gastric\ncancer cells without obvious toxicity. Therefore, Z-1 represents a\npotential novel immunomodulator that targets LSD1, providing a lead\ncompound with new function mechanism for gastric cancer treatment.