Literature summary for 1.14.11.66 extracted from

Bavetsias, V.; Lanigan, R.M.; Ruda, G.F.; Atrash, B.; McLaughlin, M.G.; Tumber, A.; Mok, N.Y.; Le Bihan, Y.V.; Dempster, S.; Boxall, K.J.; Jeganathan, F.; Hatch, S.B.; Savitsky, P.; Velupillai, S.; Krojer, T.; England, K.S.; Sejberg, J.; Thai, C.; Donovan, A.; Pal, A.; Scozzafava, G.; Bennett, J.M.; Kawamu, A.
8-Substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors (2016), J. Med. Chem., 59, 1388-1409 .

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Cloned(Commentary)

Cloned (Comment)	Organism
gene KMD4A, recombinant expression of N-terminally His-tagged KDM4A construct (residues 1-359) in Escherichia coli, recombinant expression of N-terminally GST-tagged enzyme in Spodoptera frugiperda Sf9 cells via baculovirus transfection method	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified recombinant detagged enzyme in apo form and in complex with several inhibitors, hanging drop vapor diffusion method, mixing of 0.0015 ml of 7 mg/ml protein solution with 0.0015 ml of reservoir solution containing 2-16% w/v PEG 4000 and 0.1 M BTP, pH 7.5, and equilibration against 0.8 ml, 18°C, 1 week, the crystals are then soaked by addition of 750 nL of ligand solution at 10-200 mM in DMSO directly to the crystallizatin drops, followed by 4-48 h incubation at 18°C, X-ray diffraction structure determination and analysis	Homo sapiens

Crystallization (Comment)

Organism

purified recombinant detagged enzyme in apo form and in complex with several inhibitors, hanging drop vapor diffusion method, mixing of 0.0015 ml of 7 mg/ml protein solution with 0.0015 ml of reservoir solution containing 2-16% w/v PEG 4000 and 0.1 M BTP, pH 7.5, and equilibration against 0.8 ml, 18°C, 1 week, the crystals are then soaked by addition of 750 nL of ligand solution at 10-200 mM in DMSO directly to the crystallizatin drops, followed by 4-48 h incubation at 18°C, X-ray diffraction structure determination and analysis

Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
H188A/E190A	site-directed mutagenesis, inactive mutant	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(R)-2-(1-(1-benzoylpiperidin-3-yl)-1H-1,2,3-triazol-4-yl)isonicotinic acid	-	Homo sapiens
1-(3-(ethylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one	-	Homo sapiens
1-(3-(methylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one	-	Homo sapiens
1-(4-(methylsulfonyl)phenyl)-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one	-	Homo sapiens
1-phenyl-2-(4-(pyridin-2-yl)thiazol-2-yl)ethan-1-one	-	Homo sapiens
2-(1-hydroxyvinyl)isonicotinic acid	-	Homo sapiens
2-(2-aminothiazol-4-yl)isonicotinamide	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
2-(2-aminothiazol-4-yl)isonicotinic acid	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
2-(2-benzamidothiazol-4-yl)isonicotinic acid	-	Homo sapiens
2-(2-methylthiazol-4-yl)isonicotinic acid	-	Homo sapiens
2-(thiazol-4-yl)isonicotinic acid	-	Homo sapiens
3-((2-(pyridin-2-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)pyrimidin-4-yl)amino)propanoic acid	-	Homo sapiens
3-(2-((2-aminoethyl)carbamoyl)pyridin-4-yl)benzoic acid	-	Homo sapiens
4-((methyl((1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)methyl)amino)methyl)benzonitrile	-	Homo sapiens
4-((methyl(2-(1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethyl)amino)methyl)benzonitrile	-	Homo sapiens
4-(1-(2-(1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethyl)piperidin-4-yl)benzonitrile	-	Homo sapiens
4-(pyridin-2-yl)thiazol-2-amine	low inhibition activity	Homo sapiens
4-(pyridin-3-yl)thiazol-2-amine	low inhibition activity	Homo sapiens
8-(((furan-2-ylmethyl)amino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-((4-(pyridin-2-yl)piperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-((4-methylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-((4-phenylpiperazin-1-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-((benzylamino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
8-((dimethylamino)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(1-methyl-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(2-aminothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
8-(4-(((3,4-dichlorobenzyl)(methyl)amino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-((methyl(4-(methylsulfonyl)benzyl)amino)methyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
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	Homo sapiens
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	-	Homo sapiens
8-(4-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(2-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(3,4-dichlorobenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	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	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	Homo sapiens
8-(4-(2-(4-(3,5-difluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
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	Homo sapiens
8-(4-(2-(4-(3-methoxybenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(4-(methylsulfonyl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(4-(trifluoromethyl)benzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
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	Homo sapiens
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	Homo sapiens
8-(4-(2-(4-(4-fluorobenzyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(4-fluorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(4-methoxyphenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
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	-	Homo sapiens
8-(4-(2-(4-(pyridin-3-ylmethyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(pyridin-4-yl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-benzylpiperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(2-(4-phenylpiperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(hydroxymethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(piperidin-1-ylmethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(4-(pyrrolidin-1-ylmethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(piperidin-1-ylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
8-(thiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
8-chloropyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens
lithium 2-(((furan-2-ylmethyl)amino)methyl)isonicotinate	-	Homo sapiens
lithium 2-((benzylamino)methyl)isonicotinate	enzyme-bound structure determination, crystal structure, overview	Homo sapiens
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	Homo sapiens
pyrido[3,4-d]pyrimidin-4(3H)-one	-	Homo sapiens

Localization

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

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Fe2+	dependent on, active site bound, required for activity	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
histone H3 N6,N6,N6-trimethyl-L-lysine9 + 2-oxoglutarate + O2	Homo sapiens	-	histone H3 N6,N6-dimethyl-L-lysine9 + succinate + formaldehyde + CO2	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	O75164	-	-
Homo sapiens	O94953	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant N-terminally GST-tagged enzyme from Spodoptera frugiperda Sf9 cells by glutathione affinity chromatography and gel filtration, recombinant N-terminally His-tagged KDM4A 1-359 from Escherichia coli by nickel affinity chromatography, followed by tag removal with TEV protease, another step of nickel affinity chromatography using the eluate, and gel filtration	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
Caco-2 cell	-	Homo sapiens	-
HeLa cell	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
histone H3 N6,N6,N6-trimethyl-L-lysine9 + 2-oxoglutarate + O2	-	Homo sapiens	histone H3 N6,N6-dimethyl-L-lysine9 + succinate + formaldehyde + CO2	-	?
additional information	the enzyme is also active on histone H3 N6,N6,N6-trimethyl-L-lysine36, cf. EC 1.14.11.27	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
JMJD2A	-	Homo sapiens
JMJD2B	-	Homo sapiens
KDM4A	-	Homo sapiens
KDM4B	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
22	-	assay at room temperature	Homo sapiens

pH Optimum

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