脱甲基酶
化学
吩噻嗪
药理学
氯丙嗪
癌细胞
IC50型
癌症
细胞生长
体内
程序性细胞死亡
铅化合物
细胞
体外
癌症研究
组蛋白
细胞凋亡
生物化学
生物
医学
内科学
生物技术
基因
作者
Xing‐Jie Dai,Lijuan Zhao,Longhua Yang,Ting Guo,Lei-Peng Xue,Hongmei Ren,Zhi-Li Yin,Xiao-Peng Xiong,Ying Zhou,Shi‐Kun Ji,Huimin Liu,Hong‐Min Liu,Ying Li,Yi‐Chao Zheng
标识
DOI:10.1021/acs.jmedchem.2c01593
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI