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Literature summary for 1.14.11.66 extracted from

  • Morera, L.; Roatsch, M.; Fuerst, M.C.; Hoffmann, I.; Senger, J.; Hau, M.; Franz, H.; Schuele, R.; Heinrich, M.R.; Jung, M.
    4-biphenylalanine- and 3-phenyltyrosine-derived hydroxamic acids as inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A (2016), ChemMedChem, 11, 2063-2083 .
    View publication on PubMed
Search for more literature for 1.14.11.66

Activating Compound

Activating Compound Comment Organism Structure
ascorbate
-
 Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
gene KDM4A, recombinant expression of His-tagged KDM4A residues 1-359 in Escherichia coli strain BL21 Codon-Plus-Ril from plasmid pNIC28-Bsa4 Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
2-(2-((chroman-6-ylmethyl)amino)pyrimidin-4-yl)isonicotinic acid
-
 Homo sapiens
3-(9-(dimethylamino)-N-hydroxynonanamido)propanoic acid
-
 Homo sapiens
3-[hydroxy-[5-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
-
 Homo sapiens
3-[hydroxy-[5-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
-
 Homo sapiens
3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid
-
 Homo sapiens
3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
 Homo sapiens
3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
 Homo sapiens
3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
 Homo sapiens
5-tetrazolyl acetohydrazide
-
 Homo sapiens
8-(4-(2-(4-(3,5-dichlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
-
 Homo sapiens
8-(hydroxyamino)-N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]-8-oxo-octanamide
-
 Homo sapiens
methyl (2S)-2-[[4-[3-(hydroxyamino)-3-oxo-propyl]benzoyl]amino]-3-(4-phenylphenyl)propanoate
-
 Homo sapiens
methyl (2S)-2-[[7-(hydroxyamino)-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
-
 Homo sapiens
methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
-
 Homo sapiens
methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
-
 Homo sapiens
methyl (S)-3-(2'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(3'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(4'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(4'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl (S)-3-([1,1'-biphenyl]-4-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl 3-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
 Homo sapiens
methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate
-
 Homo sapiens
additional information 4-biphenylalanine- and 3-phenyltyrosine-derived hydroxamic acids are inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A, synthesis and chemical modifications on the lead structure and biochemical evaluation, structure-activity relationships, overview. For KDM4A inhibition, the best compounds are those bearing a biphenylalanine cap (both configurations) with an additional hydroxamic acid moiety, a C8 alkyl chain as spacer, and an N-alkylated warhead for the selectivity against hydroxamate-based histone deacetylases, HDACs, methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate and 3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid. Effect of inhibitors compounds methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate, 3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid, methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate, and 3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid on on cell proliferation of KYSE-150 and HL-60 cells. Cell-permeable derivatives clearly show a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells Homo sapiens
N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]heptanamide
-
 Homo sapiens
N1-((3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)methyl)-N8-hydroxyoctanediamide
-
 Homo sapiens
N1-(2-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
-
 Homo sapiens
N1-(2-(3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
-
 Homo sapiens
SW55 a hydroxamate-based histone deacetylase (HDAC) inhibitor, slight inhibition Homo sapiens
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
-
 Homo sapiens
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-phenyl-propanoate
-
 Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
nucleus
-
 Homo sapiens 5634
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
[histone H3]-N6,N6,N6-trimethyl-L-lysine 9 + 2-oxoglutarate + O2 Homo sapiens
-
 [histone H3]-N6,N6-dimethyl-L-lysine 9 + succinate + formaldehyde + CO2
-
 ?
[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 Homo sapiens
-
 [histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens O75164
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged KDM4A residues 1-359 from Escherichia coli strain BL21 Codon-Plus-Ril by nickel affinity chromatography to over 90% purity Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
HL-60 cell
-
 Homo sapiens
-
promyelocytic leukemia cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATKAARK(me3)-SAPATGGVKKPHRYRPG-GK(biotin) + 2-oxoglutarate + O2 usage of immunodetection for assay quantification Homo sapiens ATKAARKSAPATGGVKKPHRYRPG-GK(biotin) + succinate + formaldehyde + CO2
-
 ?
additional information the bifunctional enzyme is active on H3K9me3/me2 and H3K36me3/me2 (EC 1.14.11.69) substrates. Usage of a formaldehyde dehydrogenase (FDH) enzyme-coupled demethylase activity assay Homo sapiens ?
-
 ?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 9 + 2-oxoglutarate + O2
-
 Homo sapiens [histone H3]-N6,N6-dimethyl-L-lysine 9 + succinate + formaldehyde + CO2
-
 ?
[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
-
 Homo sapiens [histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
 ?

Synonyms

Synonyms Comment Organism
JMJD2A
-
 Homo sapiens
JumonjiC-domain-containing histone demethylase
-
 Homo sapiens
KDM4A
-
 Homo sapiens
More see also EC 1.14.11.69 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
 assay at Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.003
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-(9-(dimethylamino)-N-hydroxynonanamido)propanoic acid
0.0068
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
0.0068
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate
0.0085
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 8-(hydroxyamino)-N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]-8-oxo-octanamide
0.0136
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
0.0143
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
0.0145
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens N1-((3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)methyl)-N8-hydroxyoctanediamide
0.0166
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens N1-(2-(3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
0.0171
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
0.0188
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens N1-(2-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
0.0254
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-([1,1'-biphenyl]-4-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.0254
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens SW55
0.0258
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (2S)-2-[[4-[3-(hydroxyamino)-3-oxo-propyl]benzoyl]amino]-3-(4-phenylphenyl)propanoate
0.0276
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl 3-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.029
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(3'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.037
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 2-(2-((chroman-6-ylmethyl)amino)pyrimidin-4-yl)isonicotinic acid
0.0371
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
0.0466
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 5-tetrazolyl acetohydrazide
0.0476
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.0483
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(4'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.0522
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.0548
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(4'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.056
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
0.0563
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(2'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.0606
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid
0.0703
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[5-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
0.0706
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (2S)-2-[[7-(hydroxyamino)-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
0.0939
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens methyl (S)-3-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
0.2
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens 3-[hydroxy-[5-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
0.2
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]heptanamide
0.201
-
 pH 7.5, 37°C, recombinant enzyme Homo sapiens tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-phenyl-propanoate

General Information

General Information Comment Organism
evolution the enzyme belongs to the KDM2-8 family, KDM4 (also known as JMJD2) subfamily, which divided into five isoforms A-E Homo sapiens
malfunction overexpression of the histone lysine demethylase KDM4A is related to the pathology of several human cancers Homo sapiens
physiological function the histone lysine demethylase KDM4A regulates H3K9 and H3K36 methylation states Homo sapiens