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(R)-2-(1-(1-benzoylpiperidin-3-yl)-1H-1,2,3-triazol-4-yl)isonicotinic acid
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(R)-2-hydroxyglutarate
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(S)-2-hydroxyglutarate
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1-(3-(ethylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one
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1-(3-(methylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one
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1-(4-(methylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one
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1-phenyl-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one
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2-(1-hydroxyvinyl)isonicotinic acid
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2-(2-((chroman-6-ylmethyl)amino)pyrimidin-4-yl)isonicotinic acid
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2-(2-aminothiazol-4-yl)isonicotinamide
enzyme-bound structure determination, crystal structure, overview
2-(2-aminothiazol-4-yl)isonicotinic acid
enzyme-bound structure determination, crystal structure, overview
2-(2-benzamidothiazol-4-yl)isonicotinic acid
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2-(2-methylthiazol-4-yl)isonicotinic acid
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2-(thiazol-4-yl)isonicotinic acid
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3-((2-(pyridin-2-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)pyrimidin-4-yl)amino)propanoic acid
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3-(2-((2-aminoethyl)carbamoyl)pyridin-4-yl)benzoic acid
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3-(9-(dimethylamino)-N-hydroxynonanamido)propanoic acid
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3-[hydroxy-[5-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
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3-[hydroxy-[5-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
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3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid
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3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
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3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
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3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
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4-((methyl((1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)methyl)amino)methyl)benzonitrile
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4-((methyl(2-(1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethyl)amino)methyl)benzonitrile
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4-(1-(2-(1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethyl)piperidin-4-yl)benzonitrile
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4-(pyridin-2-yl)thiazol-2-amine
low inhibition activity
4-(pyridin-3-yl)thiazol-2-amine
low inhibition activity
5-(anilinomethyl)quinolin-8-ol
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5-tetrazolyl acetohydrazide
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8-(((furan-2-ylmethyl)amino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-((4-(pyridin-2-yl)piperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-((4-methylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-((benzylamino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-((dimethylamino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(1-methyl-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(2-aminothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-(4-(((3,4-dichlorobenzyl)(methyl)amino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-((methyl(4-(methylsulfonyl)benzyl)amino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-((4-fluorobenzyl) (methyl)amino)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-(4-(2-(4-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(2-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(3,4-dichlorobenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(3,5-dichlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
8-(4-(2-(4-(3,5-difluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(3-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site, incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 8-(4-(2-(4-(3-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one which demonstrates equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay
8-(4-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(4-(methylsulfonyl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(4-(trifluoromethyl)benzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(4-chlorobenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-(4-(2-(4-(4-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-(4-(2-(4-(4-fluorobenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(4-fluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(4-methoxyphenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(pyridin-3-ylmethyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(pyridin-4-yl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-benzylpiperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-phenylpiperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(hydroxymethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(piperidin-1-ylmethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(pyrrolidin-1-ylmethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(hydroxyamino)-N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]-8-oxo-octanamide
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8-(piperidin-1-ylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(thiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview
8-chloropyrido[3,4-d]pyrimidin-4(3H)-one
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Co2+
has an activating on multiple histone modifications at the global level. Cobalt ions significantly increase global histone H3K4me3, H3K9me2, H3K9me3, H3K27me3 and H3K36me3, as well as uH2A and uH2B and decreases acetylation at histone H4 (AcH4) in vivo. Cobalt ions increase H3K9me3 and H3K36me3 by inhibiting histone demethylation process in vivo. And cobalt ions directly inhibit demethylase activity of JMJD2A in vitro. Cobalt ions do not increase the level of uH2A in the in vitro histone ubiquitinating assay and inhibit histone-deubiquitinating enzyme activity in vitro
dimethyl 4-hydroxy-1H-pyrazole-3,5-dicarboxylate
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H2O2
loss of KDM4A activity in hypoxia resulting in changes to global histone lysine methylation
lithium 2-(((furan-2-ylmethyl)amino)methyl)isonicotinate
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lithium 2-((benzylamino)methyl)isonicotinate
enzyme-bound structure determination, crystal structure, overview
methyl (2S)-2-[[4-[3-(hydroxyamino)-3-oxo-propyl]benzoyl]amino]-3-(4-phenylphenyl)propanoate
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methyl (2S)-2-[[7-(hydroxyamino)-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
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methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
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methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
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methyl (S)-3-(2'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(3'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(4'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(4'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl (S)-3-([1,1'-biphenyl]-4-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl 3-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
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methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate
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N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]heptanamide
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N1-((3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)methyl)-N8-hydroxyoctanediamide
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N1-(2-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
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N1-(2-(3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
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Peptide inhibitor
a suicide inhibitor consisting of a 21 residue histone H3 peptide in which K4 is modified by an Nmethylpropargyl group. 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 LSD1, binding structure, overview
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pyrido[3,4-d]pyrimidin-4(3H)-one
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SW55
a hydroxamate-based histone deacetylase (HDAC) inhibitor, slight inhibition
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
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tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-phenyl-propanoate
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tert-butyl benzo[b]tellurophen-2-ylmethylcarbamate
shows KDM4 specific inhibitory activity in cervical cancer HeLa cells. The compound also induces cell death in cervical and colon cancer but not in normal cells
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8-(4-(2-(4-(3,5-dichlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
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8-(4-(2-(4-(3,5-dichlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
enzyme-bound structure determination, crystal structure, overview; substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site, incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 8-(4-(2-(4-(3-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one which demonstrates equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, and cellular permeability in the Caco-2 assay
caffeic acid
a KDM4C inhibitor, that preferentially abolishes tumor-initiating cells in an ALDHbri+-derived xenograft model in vivo
N-oxalylglycine
NOG, a nonreactive 2-oxoglutarate analogue
Ni2+
substitutes for Fe(II) and inhibits the hydroxylation reaction
additional information
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pharmacological inhibition of Hsp90 promotes ubiquitin-dependent proteasomal degradation of KDM4B. Hsp90 inhibition promotes KDM4B degradation and alters the methylation of H3K9
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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
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additional information
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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
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additional information
discovery and synthesis of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Enzyme-inhibitor binding structure modeling based on structure PDB 3PDQ, and determination from crystal structure, structure-function relationships, overview. No activity with 3-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, and 4-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, poor inhibition by 8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; discovery and synthesis of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Enzyme-inhibitor binding structure modeling based on structure PDB 3PDQ, and determination from crystal structure, structure-function relationships, overview. No activity with 8-chloropyrido[3,4-d]pyrimidin-4(3H)-one, 4-(pyridin-3-yl)thiazol-2-amine, 3-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, and 4-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, poor inhibition by 4-(pyridin-2-yl)thiazol-2-amine, 8-(piperidin-1-ylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, and 8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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additional information
discovery and synthesis of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Enzyme-inhibitor binding structure modeling based on structure PDB 3PDQ, and determination from crystal structure, structure-function relationships, overview. No activity with 3-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, and 4-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, poor inhibition by 8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; discovery and synthesis of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Enzyme-inhibitor binding structure modeling based on structure PDB 3PDQ, and determination from crystal structure, structure-function relationships, overview. No activity with 8-chloropyrido[3,4-d]pyrimidin-4(3H)-one, 4-(pyridin-3-yl)thiazol-2-amine, 3-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, and 4-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide, poor inhibition by 4-(pyridin-2-yl)thiazol-2-amine, 8-(piperidin-1-ylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, and 8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
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additional information
structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36, overview
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additional information
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structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36, overview
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additional information
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histone methyltransferase SUV39h deficiency changes the association between endogenous JMJD2b and various histone marks at chromocenters, overview. The level of full-length JMJD2b at chromocenters was reduced, corresponding to a global decrease in JMJD2b and H3K9me3
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