3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors

Abstract

The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors are not toxic to mammalian cells in vitro, and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint Figure 1. Structures of LSD1 inhibitors 1, verlindamycin 2, (bis)thioureas 3, amidoxime 4, cyclic peptide 5, N3-(2-chloro-6-phenoxybenzyl)-4H-1,2,4-triazole-3,5-diamine 6 and N3,N5-bis(2-methoxybenzyl)-1H-1,2,4-triazole-3,5-diamine 7.

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

“…An important step in producing these new LSD1 inhibitors is to reduce MAO binding while retaining KDM inhibition activity [156]. The 3,5-diamino 1,2,4-triazoles similar to 33 are potent, selective and reversible inhibitors of LSD1 (IC 50 = 1-2 μM) with minimal activity toward MAO-A and MAO-B (IC 50 > 100 μM) [157]. The coumerin-1,2,3triazole dithiocarbamate hybrid 34 showed even greater potency (IC 50 = 0.39 μM LSD1) and selectivity over MAO-A and MAO-B (IC 50 >1250 μM) [158].…”

A Systematic Review of Histone Lysine‐Specific Demethylase 1 and Its Inhibitors

“…Woster disclosed 3,5‐diamino‐1,2,4‐triazoles as a novel scaffold for potent and reversible LSD1 inhibitors. With virtual screen, compound 31 was identified as cellular active LSD1 inhibitor . As reported, Sorna et al.…”

Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

“…GBM culture viability dropped within 48 h of Q-PAC treatment at concentrations of 30 lM and above ( Figure S3f). Importantly, the potent LSD1 inhibitor Triazole 6 (Kutz et al 2014) had no effect on viability, confluence or caspase activity in the primary GBM RN1 cells, and only reduced migration at 100 lM ( Figure S5). In contrast to the GBM cultures, healthy astrocytes treated with Q-PAC at concentrations up to 300 lM for 48 h showed no reduction in cell viability (F(6,53) = 0.56, p = 0.76; Figure S3f), or a change in their migratory behaviour (F(6,12) = 0.47, p = 0.82; Fig.…”