LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

CD155 as an emerging target in tumor immunotherapy.

CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape. In addition, novel therapeutic strategies and clinical trials targeting CD155 and its receptors are summarized, providing a strong rationale and way forward for the development of next-generation immunotherapies.

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.

Discovery of acridine-based LSD1 inhibitors as immune activators targeting LSD1 in gastric cancer.

LSD1 is overexpressed in various cancers and promotes tumor cell proliferation, tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC50 = 0.88 µM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC50 = 0.073 µM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.