(Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators

Shiv K. Sharma, Yu Wu, Nora Steinbergs, Michael L. Crowley, Allison S. Hanson, Robert A. Casero, Patrick M. Woster

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages5197-5212
Number of pages16
JournalJournal of Medicinal Chemistry
Volume53
Issue number14
DOIs
StatePublished - Jul 22 2010

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Thiourea
Epigenomics
Lysine
Urea
GATA4 Transcription Factor
Guanidines
Biguanides
Gene Silencing
Tumor Suppressor Genes
Antineoplastic Agents
Histones
Methylation
Chromatin
Neoplasms
Carcinoma
Gene Expression
Lung
Enzymes
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Sharma, S. K., Wu, Y., Steinbergs, N., Crowley, M. L., Hanson, A. S., Casero, R. A., & Woster, P. M. (2010). (Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. Journal of Medicinal Chemistry, 53(14), 5197-5212. DOI: 10.1021/jm100217a

(Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. / Sharma, Shiv K.; Wu, Yu; Steinbergs, Nora; Crowley, Michael L.; Hanson, Allison S.; Casero, Robert A.; Woster, Patrick M.

In: Journal of Medicinal Chemistry, Vol. 53, No. 14, 22.07.2010, p. 5197-5212.

Research output: Contribution to journalArticle

Sharma, SK, Wu, Y, Steinbergs, N, Crowley, ML, Hanson, AS, Casero, RA & Woster, PM 2010, '(Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators' Journal of Medicinal Chemistry, vol. 53, no. 14, pp. 5197-5212. DOI: 10.1021/jm100217a
Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS, Casero RA et al. (Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. Journal of Medicinal Chemistry. 2010 Jul 22;53(14):5197-5212. Available from, DOI: 10.1021/jm100217a
Sharma, Shiv K. ; Wu, Yu ; Steinbergs, Nora ; Crowley, Michael L. ; Hanson, Allison S. ; Casero, Robert A. ; Woster, Patrick M./ (Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 14. pp. 5197-5212
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