title: Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1.
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 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes 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 protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, Michigan 48202, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hazeldine
authors.forename: Boobalan
authors.initials: B
authors.lastname: Pachaiyappan
authors.forename: Nora
authors.initials: N
authors.lastname: Steinbergs
authors.forename: Shannon
authors.initials: S
authors.lastname: Nowotarski
authors.forename: Allison S
authors.initials: AS
authors.lastname: Hanson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D008970:Molecular Weight; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D010091:Oximes; D056466:Histone Demethylases; C495195:KDM1A protein, human