(Bis)urea and (Bis)thiourea Inhibitors of Lysine-Specific Demethylase 1 as Epigenetic Modulators

Abstract

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 over expression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguanides that are potent inhibitors of LSD1, and induce the reexpression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of isosteric ureas and thioureas that are also potent inhibitors of LSD1. These compounds induce increases in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related proteins (SFRP) 2 and 5, and transcription factor GATA4. These compounds represent an important new series of epigenetic modulators with the potential for use as antitumor agents.

Transcriptional Activity of the Islet β Cell Factor Pdx1 Is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9

“…The fluorophore-labeled secondary antibodies IRDye 700 and IRDye 800 were obtained from Licor Biosciences. The demethylase inhibitor BP-107-7 was synthesized using a synthetic route described previously (27,28).…”

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A

“…Also other monoamine oxidase (MAO) inhibitors, such as pargyline, have been investigated but the issue of the poor pharmacokinetic properties seemed to be unsolvable [29]. Some polyamines (CGC-11047) were evaluated as KDM1A inhibitors, with compounds showing activity in the low micromolar range [30,31]. Other compounds, not belonging to any definite series (namoline, CBB-1007), were found to be reversible KDM1A inhibitors as well [32].…”

Targeting protein lysine methylation and demethylation in cancers

“…Among these compounds, the best were polyamines 2 and 3 (Fig. 3), which inhibited LSD1 activity by 85% and 82%, respectively, at 10 mM [85,86]. Subsequently, Huang et al [87] investigated polyamines, such as PG11150 (IC 50 ¼ 5 mM), as inhibitors of LSD1.…”