Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells.

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.

Triazole-fused pyrimidines in target-based anticancer drug discovery.

In recent decades, the development of targeted drugs has featured prominently in the treatment of cancer, which is among the major causes of mortality globally. Triazole-fused pyrimidines, a widely-used class of heterocycles in medicinal chemistry, have attracted considerable interest as potential anticancer agents that target various cancer-associated targets in recent years, demonstrating them as valuable templates for discovering novel anticancer candidates. The current review concentrates on the latest advancements of triazole-pyrimidines as target-based anticancer agents, including works published between 2007 and the present (2007-2022). The structure-activity relationships (SARs) and multiple pathways are also reviewed to shed light on the development of more effective and biotargeted anticancer candidates.

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1.

As a flavin adenine dinucleotide (FAD)-dependent monoamine oxidase, lysine specific demethylase 1 (LSD1/KDM1A) functions as a transcription coactivator or corepressor to regulate the methylation of histone 3 lysine 4 and 9 (H3K4/9), and it has emerged as a promising epigenetic target for anticancer treatment. To date, numerous inhibitors targeting LSD1 have been developed, some of which are undergoing clinical trials for cancer therapy. Although only two reversible LSD1 inhibitors CC-90011 and SP-2577 are in the clinical stage, the past decade has seen remarkable advances in the development of reversible LSD1 inhibitors. Herein, we provide a comprehensive review about structures, biological evaluation, and structure-activity relationship (SAR) of reversible LSD1 inhibitors.

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective.

Histone lysine-specific demethylase 1 (LSD1/KDM1A) has become an important and promising anticancer target since it was first identified in 2004 and specially demethylates lysine residues of histone H3K4me1/2 and H3K9me1/2. LSD1 is ubiquitously overexpressed in diverse cancers, and abrogation of LSD1 results in inhibition of proliferation, invasion, and migration in cancer cells. Over the past decade, a number of biologically active small-molecule LSD1 inhibitors have been developed. To date, six trans-2-phenylcyclopropylamine (TCP)-based LSD1 inhibitors (including TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, and ORY-2001) that covalently bind to the flavin adenine dinucleotide (FAD) within the LSD1 catalytic cavity have already entered into clinical trials. Here, we provide an overview about the structures, activities, and structure-activity relationship (SAR) of TCP-based LSD1 inhibitors that mainly covers the literature from 2008 to date. The opportunities, challenges, and future research directions in this emerging and promising field are also discussed.