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PDBsum entry 5f3c
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Oxidoreductase
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PDB id
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5f3c
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References listed in PDB file
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Key reference
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Title
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8-Substituted pyrido[3,4-D]pyrimidin-4(3h)-One derivatives as potent, Cell permeable, Kdm4 (jmjd2) and kdm5 (jarid1) histone lysine demethylase inhibitors.
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Authors
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V.Bavetsias,
R.M.Lanigan,
G.F.Ruda,
B.Atrash,
M.G.Mclaughlin,
A.Tumber,
N.Y.Mok,
Y.V.Le bihan,
S.Dempster,
K.J.Boxall,
F.Jeganathan,
S.B.Hatch,
P.Savitsky,
S.Velupillai,
T.Krojer,
K.S.England,
J.Sejberg,
C.Thai,
A.Donovan,
A.Pal,
G.Scozzafava,
J.M.Bennett,
A.Kawamura,
C.Johansson,
A.Szykowska,
C.Gileadi,
N.A.Burgess-Brown,
F.Von delft,
U.Oppermann,
Z.Walters,
J.Shipley,
F.I.Raynaud,
S.M.Westaway,
R.K.Prinjha,
O.Fedorov,
R.Burke,
C.J.Schofield,
I.M.Westwood,
C.Bountra,
S.Müller,
R.L.Van montfort,
P.E.Brennan,
J.Blagg.
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Ref.
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J Med Chem, 2016,
59,
1388-1409.
[DOI no: ]
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PubMed id
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Abstract
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We report the discovery 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. 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 54j and 54k
which demonstrate 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, for
54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
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