1.14.99.66: [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase
This is an abbreviated version!
For detailed information about [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase, go to the full flat file.
Word Map on EC 1.14.99.66
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1.14.99.66
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chromatin
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demethylation
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corest
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corepressors
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deacetylases
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chromatin-modifying
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tranylcypromine
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lsd1-mediated
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lys4
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demethylase-1
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di-methylated
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swirm
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h3k4me1
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pargyline
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diagnostics
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drug development
- 1.14.99.66
- chromatin
-
demethylation
- corest
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corepressors
- deacetylases
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chromatin-modifying
- tranylcypromine
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lsd1-mediated
- lys4
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demethylase-1
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di-methylated
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swirm
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h3k4me1
- pargyline
- diagnostics
- drug development
Reaction
Synonyms
amine oxidase flavin-containing domain 1, amine-oxidase flavin-containing domain 1, AOF1, AOF2, BHC110, BHC110/LSD1, CG9088, demethylase LSD1, dJARID1/Lid, H3K4 demethylase, H3K4me2 demethylase, H3K4me2/1 histone demethylase, histone demethylase, histone H3 K4 demethylase, histone H3 lysine 4 demethylase, histone H3K4 demethylase, histone lysine-specific demethylase 1, Jarid1, KDM1, KDM1A, KDM1B, KIAA0601, LD40310, Lid, LSD1, LSD1 demethylase, LSD1/KDM1, LSD1/KDM1A, LSD2, lysine demethylase 1B, lysine specific demethylase 1, lysine-specific demethylase 1, lysine-specific demethylase 1A, lysine-specific demethylase 2, lysine-specific demethylase-1, lysine-specific histone demethylase, lysine-specific histone demethylase 1, lysine-specific histone demethylase 1A, lysine-specific histone demethylase 1B, lysinespecific demethylase 1, More, SPR-5
ECTree
1.14.99.66 [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylaseAdvanced search results
results (
results (Inhibitors
Inhibitors on EC 1.14.99.66 - [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase
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INHIBITOR 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
IMAGE
(2-hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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(2-hydroxyacetyl)-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
1,1'-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[3-(2,2-diphenylethyl)guanidine]
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1,1'-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[3-(3,3-diphenylpropyl)guanidine]
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1,1'-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis(3-methylguanidine)
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1,1'-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis(3-phenylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(2,3-dimethylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(3-methylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(3-phenylguanidine)
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1,11-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,8-diazaundecane
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48.9% inhibition at 0.01 mM
1,11-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,8-diazaundecane
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75.2% inhibition at 0.01 mM
1,11-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,8-diazaundecane
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7.8% inhibition at 0.01 mM
1,11-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,8-diazaundecane
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7.1% inhibition at 0.01 mM
1,11-bis-[3-[1-(benzyl)thioureado]]-4,8-diazaundecane
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47.9% inhibition at 0.01 mM
1,11-bis-[3-[1-(ethyl)thioureado]]-4,8-diazaundecane
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63.8% inhibition at 0.01 mM
1,11-bis-[3-[1-(n-propyl)ureado]]-4,8-diazaundecane
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48.7% inhibition at 0.01 mM
1,11-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,8-diazaundecane
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8.5% inhibition at 0.01 mM
1,12-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,9-diazadodecane
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65.6% inhibition at 0.01 mM
1,12-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,9-diazadodecane
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82.9% inhibition at 0.01 mM
1,12-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,9-diazadodecane
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21.4% inhibition at 0.01 mM
1,12-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,9-diazadodecane
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25.4% inhibition at 0.01 mM
1,12-bis-[3-[1-(ethyl)thioureado]]-4,9-diazadodecane
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60% inhibition at 0.01 mM
1,12-bis-[3-[1-(n-propyl)thioureado]]-4,9-diazadodecane
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10.4% inhibition at 0.01 mM
1,12-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,9-diazadodecane
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73.9% inhibition at 0.01 mM
1,15-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,12-diazapentadecane
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71.1% inhibition at 0.01 mM
1,15-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,12-diazapentadecane
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80.5% inhibition at 0.01 mM
1,15-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,12-diazapentadecane
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22.7% inhibition at 0.01 mM
1,15-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,12-diazapentadecane
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48.5% inhibition at 0.01 mM
1,15-bis-[3-[1-(benzyl)thioureado]]-4,12-diazapentadecane
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64.1% inhibition at 0.01 mM
1,15-bis-[3-[1-(n-propyl)ureado]]-4,12-diazapentadecane
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8.5% inhibition at 0.01 mM
1,15-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,12-diazapentadecane
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30.0% inhibition at 0.01 mM
3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide
compound increases H3K4 methylation in the brain without causing hematological side effects. Compound increases brain H3K4 methylation and partially restores learning function in mice with NMDA receptor hypofunction. Compound has minimal impact on the LSD1-GFI1B complex in human TF-1alpha erythroblasts
3-[(E)-2-[2-(5-fluoro-2-hydroxyphenyl)pyridin-4-yl]ethenyl]N'-hydroxybenzene-1-carboximidamide
potently inhibits LSD1 in a reversible and FAD competitive manner. Compound is capable of upregulating the expression of the surrogate cellular biomarker CD86 in THP-1 human leukemia cells and shows good inhibition against THP-1 and MOLM-13 cells with IC50 values of 5.76 and 8.34 microM
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzamide
tranylcypromine-based inhibitor with selectivity for LSD1 over MAO-A and MAO-B
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzene-1-sulfonamide
tranylcypromine-based inhibitor with selectivity for LSD1 over MAO-A and MAO-B
biguanide
inhibits LSD1 and is capable of reactivating genes that are pathologically silenced in the development of colon cancer
bisguanidine polyamine analogues
inhibit LSD1 and are capable of reactivating genes that are pathologically silenced in the development of colon cancer
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HCF-1
a component of the Set1 and MLL1 histone H3 Lys4 methyltransferase complexes, which coordinates modulation of repressive H3 Lys9 methylation levels with addition of activating H3 Lys4 trimethylation marks
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histone H3
full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor; full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor of KDM1A demethylation activity with a Ki of 18.9 nM, a value that is approximately 100fold higher than that of the 21-mer peptide of H3. The relative H3 affinity is independent of preincubation time, suggesting that H3 rapidly reaches equilibrium with KDM1A, tight-binding nature of the H3/KDM1A interaction, kinetics, overview. No other core histones exhibits inhibition of KDM1A demethylation activity, which is consistent with H3 being the preferred histone substrate of KDM1A versus H2A, H2B, and H4. Inhibition profiling of full-length histone H3 against KDM1A
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histone H3-1-21
peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3, competitive inhibitor
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L-alanyl-L-arginyl-L-threonyl-6-(aziridin-1-yl)norleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
compound 2 decomposes when lyophilized to dryness
L-alanyl-L-arginyl-L-threonyl-6-hydroxynorleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
a peptide containing an oxa-analogue of lysine at the fourth position of a 21 amino acid N-terminal histone H3 tail
L-alanyl-L-arginyl-L-threonyl-6-[(methylsulfonyl)oxy]norleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
mesylate peptide
L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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L-alanyl-L-arginyl-L-threonyl-N6-(prop-2-yn-1-yl)lysyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
a propargyl-Lys-derivatized peptide, MALDI-TOF spectrum of inhibitor-FAD conjugate, the reduced FAD (FADH2) undergoes nucleophilic attack on the propargylic imine and creates the covalent adduct
L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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L-homoseryseryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-homoseryl))-L-lysine
enzyme binding structure, overview
L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
enzyme binding structure, overview
N,N''''-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N,N''''-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N,N''''-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
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N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(2-hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
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N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(2-hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-(N6-(L-seryl))-L-lysyl-L-glutaminyl-L-leucine
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N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-seryl))-L-lysine-amide
enzyme binding structure, overview
N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanyl-L-threonyl-(N6-(L-seryl))-L-lysine-amide
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PCPA-Lys-4 H3-11
11-mer histone H3 peptide because the 11-mer bearing a trans-2-phenylcyclopropylamine moiety at Lys-4
PCPA-Orn-4 H3-11
11-mer histone H3 peptide because the 11-mer bearing a trans-2-phenylcyclopropylamine moiety at Orn-4
peptide H3K4M
the modified H3 peptide with substitution of Lys4 to Met [H3K4M] is known to be a potent competitive inhibitor of LSD1
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Phenelzine
inhibitor targets both the flavin adenine dinucleotide and CoREST binding domains of LSD1. Treatment reduces nuclear demethylase activity and increases transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model
[histone H3 peptide 21mer]-L-lysine4
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the demethylated peptide, product of the LSD2 reaction, inhibits LSD2
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(19E)-N,N'-diethyl-6,12,17,22,27,33-hexaazaoctatriacont-19-ene-1,38-diamine
i.e PG-11144, exhibits competitive inhibition kinetics at concentrations below 0.010 mmol/l. PG-11144 combined with a DNMT inhibitor increases H3K4 methylation and profoundly inhibits growth of established tumors in vivo
(19Z)-N,N'-diethyl-6,12,17,22,27,33-hexaazaoctatriacont-19-ene-1,38-diamine
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(25E)-N,N'-diethyl-5,11,17,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25E)-N,N'-diethyl-5,11,17,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25Z)-N,N'-diethyl-6,12,18,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25Z)-N,N'-diethyl-6,12,18,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
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(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
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(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
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trans-2-phenylcyclopropylamine
i.e. tranylcypromine; Parnate. Mechanism-based suicide inactivator, inactivation of LSD1 occurs with similar rates as the demethylation of substrates
tranylcypromine
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inhibits LSD1 by forming a covalent adduct with the flavin moiety through the opening of the inhibitor cyclopropyl ring, binding structure, overview
tranylcypromine
inhibits LSD1 by forming a covalent adduct with the flavin moiety through the opening of the inhibitor cyclopropyl ring, binding structure, overview
tranylcypromine
i.e. Parnate, binding structure analysis and modeling, overview. The LSD1-tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate. LSD1-flavin is the only place modified by this inhibition
tranylcypromine
an amino oxidase inhibitor, upregulates hTERT expression and telomerase activity concomitant with elevated H3K4me2 levels and H3 acetylation at the hTERT proximal promoter in cancer cells
additional information
phosphorylation of the H3Ser10 residue totally abolishes the AtLSD1 demethylase activity toward the H3K4me1 peptide
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additional information
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phosphorylation of the H3Ser10 residue totally abolishes the AtLSD1 demethylase activity toward the H3K4me1 peptide
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additional information
design and development of LSD1 inhibitors, overview
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additional information
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oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes, overview. Treatment of HCT-116 colon adenocarcinoma cells in vitro results in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark
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additional information
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(bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators with the potential for use as antitumor agents, overview. No inhibition by 7 and 17, poor inhibition by 11
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additional information
besides histone H3, no other core histones exhibit inhibition of KDM1A demethylation activity; KDM1A tolerance for 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) at 0.01% w/v and dimethyl sulfoxide (DMSO) at 10% v/v
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additional information
structural analysis of homoserine-substituted inhibitor peptide-bound LSD1-CoREST complex, overview
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additional information
demethylation activity is decreased by other modifications on the H3 tail, such as acetylation and phosphorylation, suggesting possible regulatory mechanisms
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additional information
a suicide inhibitor consisting of a 21-residue histone H3 peptide, in which K4 is modified by an N-methylpropargyl group, forms a covalent adduct with the reactive N5 atom of the flavin isoalloxazine ring via the N-methylpropargyl group, permitting the visualization of the first seven residues in the histone H3 peptide in the crystal structure. The residues adopt three successive gamma-turns, resulting in an approximately W-shaped conformation of the H3 peptide backbone. The inhibitor and LSD1 interact through a series of main and side chain hydrogen bonds and van der Waals contacts, further stabilizing the compact conformation of the H3 peptide. Notable interactions with the inhibitor include hydrogen bonds to its R2 and Q5 side chains and a salt bridge interaction between the alpha-amine of A1 and Asp555 in LSD. The addition of acetyl or glycyl blocking groups to the N-terminus of the H3K4me2 peptide or the substitution of the epsilon-amine of A1 with a methyl group disrupts the ionic interaction between Asp555 in LSD1 and the H3 peptide alpha-amine, diminishing specificity over 20fold. And analysis of the LSD1/CoREST-C complex co-crystallized with a 20-residue histone H3 peptide inhibitor in which Lys4 is mutated to a methionine (H3K4M). The overall conformation of the H3K4M peptide is roughly U-shaped, a binding mode that is strikingly different than the gamma-turn geometry adopted by the suicide inhibitor. The peptide's binding is stabilized by a complex network of intramolecular hydrogen bonds and intermolecular hydrogen bonds and van der Waals contacts with residues comprising the substrate binding cleft of LSD1. In particular, multiple hydrogen bonds and salt bridge interactions with the guanidinium groups of R2 and R8 in H3K4M appear to be important in maintaining the peptide's conformation and interactions with LSD1. This binding mode positions M4, which functions as a methyllysine mimic, into the pocket adjacent to the flavin moiety of FAD. Modeling of K4me2 based on the coordinates of the M4 side chain indicates that the dimethyl epsilon-amine group is at an appropriate distance for hydride transfer to the N5 atom in the FAD isoalloxazine ring
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additional information
trans-2-phenylcyclopropylamine-modified peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors
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additional information
small molecule inhibitors of LSD1 inhibit xenograft tumor growth
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additional information
oligoamine analogues are competitive inhibitors of recombinant LSD1. Oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes, overview. Treatment of HCT-116 colon adenocarcinoma cells in vitro results in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Use of LSD1 inhibitors in combination with a DNA methyltransferase (DNMT) inhibitors (5-aza-2'-deoxycitidine and 5-azacytidine) is a combination that is not only more efficacious in reactivating specific aberrantly silenced genes but also leads to profound inhibition of the growth of established human colon cancer xenografts in a nude mouse model
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additional information
N-substituted tranylcypromine derivatives without a basic function or even a polar group are potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture, but block the structurally related monoamine oxidases. The introduction of a polar, non-basic function leads to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells
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additional information
inhibitor synthesis and proposed inactivation mechanism of LSD1, overview
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additional information
histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by LSD1 in vitro. In vivo analysis reveals an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Histone H3K4 demethylation is a secondary target of HDAC inhibitors
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additional information
depletion of LSD1 or inhibition of its activity with monoamine oxidase inhibitors (MAOIs) results in the accumulation of repressive chromatin and a block to viral gene expression
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additional information
biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (SFRPs) and the GATA family of transcription factors. Reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. Inhibition detection via global H3K4me1 and H3K4me2 levels. HCT116 cells are exposed to increasing concentrations of the indicated compound for 48 h,and 00.03 mg of nuclear protein per lane is analyzed for expression of H3K4me1, H3K4me2, and H3K9me2, overview. Exposure to compounds 1c and 2d produces significant increases in both H3K4me1 and H3K4me2, without affecting global H3K9me2 levels
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in p53-null mice, LSD1 binding is depleted, H3K4me2 is increased, and H3K9me2 remains unchanged compared to those of the wild type
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TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation
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