Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer
Bo Wang, Shuwu Wang, Ying Zhou, Shaopeng Wang, Ya Gao, Huimin Liu, Shi‐Kun Ji, Saiqi Wang, Yi‐Chao Zheng, Cheng Zhang, Adil Mardinoğlu, Hong‐Min Liu, Xiaobing Chen, Xing‐Jie Dai
Abstract
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 (IC 50 = 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.