A selective phenelzine analogue inhibitor of histone demethylase LSD1

Polina Prusevich, Jay H. Kalin, Shonoi A. Ming, Manuela Basso, Jeffrey Givens, Xin Li, Jianfei Hu, Martin S. Taylor, Anne M. Cieniewicz, Po Yuan Hsiao, Rong Huang, Heather Roberson, Nkosi Adejola, Lindsay B. Avery, Robert A. Casero, Sean D. Taverna, Jiang Qian, Alan J. Tackett, Rajiv R. Ratan, Oliver G. McDonaldAndrew P. Feinberg, Philip A. Cole

Research output: Contribution to journalArticle

Abstract

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)1284-1293
Number of pages10
JournalACS chemical biology
Volume9
Issue number6
DOIs
StatePublished - Jun 20 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Prusevich, P., Kalin, J. H., Ming, S. A., Basso, M., Givens, J., Li, X., Hu, J., Taylor, M. S., Cieniewicz, A. M., Hsiao, P. Y., Huang, R., Roberson, H., Adejola, N., Avery, L. B., Casero, R. A., Taverna, S. D., Qian, J., Tackett, A. J., Ratan, R. R., ... Cole, P. A. (2014). A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS chemical biology, 9(6), 1284-1293. https://doi.org/10.1021/cb500018s