Shen Liang, Wang Bo, Wang Shao-Peng, Ji Shi-Kun, Fu Meng-Jie, Wang Shu-Wu, Hou Wen-Qing, Dai Xing-Jie, Liu Hong-Min
Key Lab of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, Henan, China.
J Med Chem. 2024 Jan 25;67(2):922-951. doi: 10.1021/acs.jmedchem.3c02133. Epub 2024 Jan 12.
Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.
赖氨酸特异性去甲基化酶1（LSD1）是一种转录调节因子，可抑制或激活靶基因表达，在许多癌症中过度表达，并导致正常基因网络表达失衡。二十多年来，已报道了许多LSD1抑制剂，其中一些已进入临床试验，包括8种不可逆抑制剂（TCP、ORY-1001、GSK-2879552、INCB059872、IMG-7289、ORY-2001、TAK-418和LH-1802）和2种可逆抑制剂（CC-90011和SP-2577）。大多数临床LSD1抑制剂与其他药物联合使用时显示出增强的疗效。也有LSD1多靶点抑制剂的报道，如临床双LSD1/组蛋白去乙酰化酶（HDAC）抑制剂4SC-202和JBI-802。在此，我们全面概述了LSD1抑制剂与各种抗肿瘤药物的联合应用，以及LSD1多靶点抑制剂。此外，还讨论了面临的挑战和未来的研究方向，我们希望这篇综述能为LSD1靶向抗癌药物的开发提供新的见解。
