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PDBsum entry 4xrx
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4xrx
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References listed in PDB file
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Key reference
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Title
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Inhibition of cancer-Associated mutant isocitrate dehydrogenases by 2-Thiohydantoin compounds.
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Authors
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F.Wu,
H.Jiang,
B.Zheng,
M.Kogiso,
Y.Yao,
C.Zhou,
X.N.Li,
Y.Song.
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Ref.
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J Med Chem, 2015,
58,
6899-6908.
[DOI no: ]
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PubMed id
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Abstract
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Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently
found in certain cancers such as glioma. With losing the activity of wild-type
IDH1, the R132H and R132C mutant proteins can reduce α-ketoglutaric acid
(α-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of
D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases,
to cause broad histone hypermethylation. These aberrant epigenetic changes are
responsible for the initiation of these cancers. We report the synthesis,
structure-activity relationships, enzyme kinetics, and binding thermodynamics of
a novel series of 2-thiohydantoin and related compounds, among which several
compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray
crystal structures of IDH1(R132H) in complex with two inhibitors are reported,
showing their inhibitor-protein interactions. These compounds can decrease the
cellular concentration of D2HG, reduce the levels of histone methylation, and
suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1
R132H mutation.
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