(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 overexpression 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 re-expression 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 protein (SFRP) 2 and transcription factor GATA4. These compounds represent an important new series of epigenetic modulators with the potential for use as antitumor agents.
Authors	Shiv K Sharma, Yu Wu, Nora Steinbergs, Michael L Crowley, Allison S Hanson, Robert A Casero, Patrick M Woster
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 14 Pg. 5197-212 (Jul 22 2010) ISSN: 1520-4804 [Electronic] United States
PMID	20568780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents GATA4 Transcription Factor Membrane Proteins Recombinant Proteins SFRP2 protein, human Urea Histone Demethylases KDM1A protein, human Thiourea
Topics	Antineoplastic Agents (chemical synthesis, pharmacology) Cell Line, Tumor Cell Survival (drug effects) Drug Screening Assays, Antitumor Epigenesis, Genetic GATA4 Transcription Factor (metabolism) Histone Demethylases (antagonists & inhibitors) Humans Membrane Proteins (metabolism) Methylation Recombinant Proteins (antagonists & inhibitors) Structure-Activity Relationship Thiourea (analogs & derivatives, chemical synthesis, pharmacology) Urea (analogs & derivatives, chemical synthesis, pharmacology)

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