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. McDonald; Andrew P. Feinberg; Philip A. Cole

doi:10.1021/cb500018s

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

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 language	English (US)
Pages (from-to)	1284-1293
Number of pages	10
Journal	ACS chemical biology
Volume	9
Issue number	6
DOIs	https://doi.org/10.1021/cb500018s
State	Published - Jun 20 2014

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/cb500018s

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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

Prusevich, P, Kalin, JH, Ming, SA, Basso, M, Givens, J, Li, X, Hu, J, Taylor, MS, Cieniewicz, AM, Hsiao, PY, Huang, R, Roberson, H, Adejola, N, Avery, LB, Casero, RA, Taverna, SD, Qian, J, Tackett, AJ, Ratan, RR, McDonald, OG, Feinberg, AP & Cole, PA 2014, 'A selective phenelzine analogue inhibitor of histone demethylase LSD1', ACS chemical biology, vol. 9, no. 6, pp. 1284-1293. https://doi.org/10.1021/cb500018s

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title = "A selective phenelzine analogue inhibitor of histone demethylase LSD1",

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.",

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

year = "2014",

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doi = "10.1021/cb500018s",

language = "English (US)",

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T1 - A selective phenelzine analogue inhibitor of histone demethylase LSD1

AU - Prusevich, Polina

AU - Kalin, Jay H.

AU - Ming, Shonoi A.

AU - Basso, Manuela

AU - Givens, Jeffrey

AU - Li, Xin

AU - Hu, Jianfei

AU - Taylor, Martin S.

AU - Cieniewicz, Anne M.

AU - Hsiao, Po Yuan

AU - Huang, Rong

AU - Roberson, Heather

AU - Adejola, Nkosi

AU - Avery, Lindsay B.

AU - Casero, Robert A.

AU - Taverna, Sean D.

AU - Qian, Jiang

AU - Tackett, Alan J.

AU - Ratan, Rajiv R.

AU - McDonald, Oliver G.

AU - Feinberg, Andrew P.

AU - Cole, Philip A.

PY - 2014/6/20

Y1 - 2014/6/20

N2 - 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.

AB - 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.

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A selective phenelzine analogue inhibitor of histone demethylase LSD1

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