Discovery of 2‑Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer

LSD1
(histone lysine-specific demethylase 1) has been gradually
disclosed to act as an immunomodulator to enhance antitumor immune
response. Despite the identification of numerous potent LSD1 inhibitors,
there remains a lack of LSD1 inhibitors approved for marketing. Novel
LSD1 inhibitors with different mechanisms are therefore needed. Herein,
we reported a series of novel quinazoline-based LSD1 inhibitors. Among
them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC50 = 0.108 μM). Z-1 also acted as a selective and cellular
active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of
gastric cancer cells to T-cell killing effect by decreasing PD-L1
expression and further attenuated the PD-1/PD-L1 interaction. In vivo,
Z-1 exhibited significant suppression effect on the growth of gastric
cancer cells without obvious toxicity. Therefore, Z-1 represents a
potential novel immunomodulator that targets LSD1, providing a lead
compound with new function mechanism for gastric cancer treatment.