LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials

by Selleckchem | May 13 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.

Comments：

Histone lysine-specific demethylase 1 (LSD1/KDM1A) is an epigenetic enzyme that plays a critical role in regulating gene expression by removing methyl groups from specific lysine residues of histone H3. LSD1 is overexpressed in many types of cancers, leading to block of differentiation and increase of proliferation, migration, and invasiveness at the cellular level. Therefore, LSD1 has emerged as a promising therapeutic target for cancer treatment.

LSD1 inhibitors can be classified into two groups: covalent and non-covalent agents. Covalent inhibitors bind to the FAD cofactor, which is essential for LSD1 activity, and irreversibly inhibit the enzyme. Non-covalent inhibitors, on the other hand, bind to other regions of the enzyme and reversibly inhibit its activity.

Several LSD1 inhibitors have been identified, and nine of them have entered clinical trials for hematological and/or solid cancers. Among these inhibitors, seven covalently bind to the FAD cofactor, while two are non-covalent. Additionally, some compounds have been identified as LSD1/MAO-B dual inhibitors, which may have potential therapeutic applications in Alzheimer's disease and personality disorders.

The clinical potential of LSD1 inhibitors lies in their ability to selectively target cancer cells, while sparing normal cells. LSD1 inhibitors have shown promise in preclinical studies, and early-phase clinical trials have demonstrated their safety and efficacy in patients with various types of cancer.

In conclusion, LSD1 is a critical epigenetic enzyme that plays a significant role in cancer progression, and LSD1 inhibitors have emerged as a promising therapeutic strategy for cancer treatment. The development of potent and selective LSD1 inhibitors, including covalent and non-covalent agents, may have significant clinical implications in the treatment of cancer and other diseases.