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PDBsum entry 5e80
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Lipid binding protein
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PDB id
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5e80
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References listed in PDB file
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Key reference
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Title
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Identification of pyrazolopyridazinones as pdeδ inhibitors.
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Authors
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B.Papke,
S.Murarka,
H.A.Vogel,
P.Martín-Gago,
M.Kovacevic,
D.C.Truxius,
E.K.Fansa,
S.Ismail,
G.Zimmermann,
K.Heinelt,
C.Schultz-Fademrecht,
A.Al saabi,
M.Baumann,
P.Nussbaumer,
A.Wittinghofer,
H.Waldmann,
P.I.Bastiaens.
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Ref.
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Nat Commun, 2016,
7,
11360.
[DOI no: ]
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PubMed id
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Abstract
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The prenyl-binding protein PDEδ is crucial for the plasma membrane localization
of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin
binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the
plasma membrane, thereby affecting the proliferation of KRas-dependent human
pancreatic ductal adenocarcinoma cell lines. Here, using structure-based
compound design, we have now identified pyrazolopyridazinones as a novel,
unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high
affinity, thereby displacing prenylated Ras proteins in cells. Our results show
that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits
less unspecific cytotoxicity than the previously reported Deltarasin and
demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in
a set of human pancreatic cancer cell lines.
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