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PDBsum entry 4l34
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Transferase/transferase inhibitor
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PDB id
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4l34
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References listed in PDB file
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Key reference
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Title
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Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity.
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Authors
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M.Narwal,
J.Koivunen,
T.Haikarainen,
E.Obaji,
O.E.Legala,
H.Venkannagari,
P.Joensuu,
T.Pihlajaniemi,
L.Lehtiö.
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Ref.
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J Med Chem, 2013,
56,
7880-7889.
[DOI no: ]
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PubMed id
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Abstract
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Tankyrases are ADP-ribosyltransferases that play key roles in various cellular
pathways, including the regulation of cell proliferation, and thus, they are
promising drug targets for the treatment of cancer. Flavones have been shown to
inhibit tankyrases and we report here the discovery of more potent and selective
flavone derivatives. Commercially available flavones with single substitutions
were used for structure-activity relationship studies, and cocrystal structures
of the 18 hit compounds were analyzed to explain their potency and selectivity.
The most potent inhibitors were also tested in a cell-based assay, which
demonstrated that they effectively antagonize Wnt signaling. To assess
selectivity, they were further tested against a panel of homologous human
ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM
potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling
inhibition. This work forms a basis for rational development of flavones as
tankyrase inhibitors and guides the development of other structurally related
inhibitors.
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