Noce Beatrice, Di Bello Elisabetta, Fioravanti Rossella, Mai Antonello
Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy.
Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
Front Pharmacol. 2023 Feb 2;14:1120911. doi: 10.3389/fphar.2023.1120911. eCollection 2023.
Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents.
组蛋白赖氨酸特异性去甲基化酶1（LSD1/KDM1A）于2004年首次被鉴定为一种表观遗传酶，它能够以黄素腺嘌呤二核苷酸（FAD）作为辅因子，使组蛋白H3的特定赖氨酸残基去甲基化，即H3K4me1/2和H3K9me1/2。它在多种癌症（乳腺癌、胃癌、前列腺癌、肝细胞癌、食管癌、急性髓系白血病等）中普遍过度表达，导致细胞水平的分化受阻以及增殖、迁移和侵袭能力增强。LSD1抑制剂可分为共价和非共价两类。每一类都包括一些杂合化合物，它们除了能抑制LSD1外，还能同时作用于其他靶点（双重或多靶点化合物）。迄今为止，已有9种LSD1抑制剂进入血液系统和/或实体癌的临床试验阶段。其中7种（反苯环丙胺、伊达司他（ORY-1001）、波美司他（IMG-7289）、GSK-2879552、INCB059872、JBI-802和苯乙肼）与FAD辅因子共价结合，另外两种是非共价LSD1抑制剂[普尔司他（CC-90011）和塞利司他（SP-2577）]。另一种基于反苯环丙胺的LSD1/单胺氧化酶B双重抑制剂瓦非司他（ORY-2001）正在进行阿尔茨海默病和人格障碍的临床试验。本综述总结了LSD1的结构和功能、其在癌症和非癌症疾病中的病理意义，以及具有不同化学结构的LSD1共价和非共价抑制剂的鉴定，包括那些参与临床试验的抑制剂，突出了它们作为强效和选择性抗癌药物的潜力。
