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Literature summary for 1.14.11.67 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 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.14.11.67

Protein Variants

Protein Variants Comment Organism
H499A/E501A site-directed mutagenesis, inactive mutant Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(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
-
 Homo sapiens
2-(2-aminothiazol-4-yl)isonicotinic acid
-
 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
3-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide
-
 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-(methylsulfonyl)-N-(4-(pyridin-3-yl)thiazol-2-yl)benzamide
-
 Homo sapiens
4-(pyridin-3-yl)thiazol-2-amine
-
 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
-
 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
-
 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
-
 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 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
-
 Homo sapiens
8-(4-(2-(4-(4-chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
-
 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
-
 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
-
 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. No inhibition by 4-(pyridin-2-yl)thiazol-2-amine; 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. No inhibition by 4-(pyridin-2-yl)thiazol-2-amine, 4-((methyl((1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)methyl)amino)methyl)benzonitrile, and 4-((methyl(2-(1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethyl)amino)methyl)benzonitrile, poor inhibition by 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-lysine4 + 2-oxoglutarate + O2 Homo sapiens
-
 histone H3 N6,N6-dimethyl-L-lysine4 + succinate + formaldehyde + CO2
-
 ?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2 Homo sapiens
-
 histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
 ?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2 Homo sapiens
-
 histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P41229
-
-
Homo sapiens Q9UGL1
-
-

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-lysine4 + 2-oxoglutarate + O2
-
 Homo sapiens histone H3 N6,N6-dimethyl-L-lysine4 + succinate + formaldehyde + CO2
-
 ?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
-
 Homo sapiens histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
 ?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
-
 Homo sapiens histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
 ?

Synonyms

Synonyms Comment Organism
JARID1B
-
 Homo sapiens
JARID1C
-
 Homo sapiens
KDM5B
-
 Homo sapiens
KDM5C
-
 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