A Selective Inhibitor of Histone Demethylase LSD1

Case ID:
C12859
Disclosure Date:
1/10/2014
Description:
UNMET NEED: 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 analogs of a monoamine oxidase antidepressant, and their LSD1 inhibitory properties. Treatment of two cancer cell lines, LNCaP and H460 with the compound conferred a reduction in proliferation rate, and the compound 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 the compound, suggesting potential applications in neurodegenerative disease.
 
TECHNICAL DESCRIPTION: This technology is a novel composition (bizine) and its use as a lysine-specific demethylase LSD1 inhibitor for the treatment of cancer and neurodegenerative diseases. Johns Hopkins researchers have developed a series of phenelzine analogs and tested their use as inhibitors of LSD1. A novel phenelzine analog (bizine) exhibits potency and selectivity for LSD1 versus monoamine oxidases A/B and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Treatment of two cancer cell lines with bizine showed a reduction in proliferation rate, and bizine showed additive synergistic effects on cell growth when used in combination with two HDAC inhibitors. Neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.
 
MAJOR RESULTS:
1. It exhibits selectivity for LSD1 versus monoamine oxidases A/B and the LSD1 homolog, LSD2.
2. It can be used in combination with histone deacetylase inhibitors to reduce cancer cell proliferation.
3. It might have potential applications in neurodegenerative diseases.
 
DISEASE INDICATION: Cancer/Neurodegenerative Diseases
 
INVENTORS: Philip Cole, Raman Bakshi, Shonoi Ming, Jay Kalin, Polina Prusevich
 
PATENT STATUS: Pending US application #15/124,208
 
ASSOCIATED PUBLICATIONS: ACS Chem Biol. 2014 Jun 20;9(6):1284-93.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty Canada 2,941,716   3/9/2015     Abandoned
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty Australia 2015226881   3/9/2015     Abandoned
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty European Patent Office 15758257.8   3/9/2015     Abandoned
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty China 201580022402.4   3/9/2015     Abandoned
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty Japan 2016-573721   3/9/2015     Abandoned
A Selective Phenelzine Analog Inhibitor of Histone Demethylase LSD1 PCT: Patent Cooperation Treaty United States 15/124,208 9/7/2016     Pending
Inventors:
Category(s):
For Information, Contact:
Vera Sampels
vsampel2@jhu.edu
410-614-0300
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