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PDBsum entry 4l02
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Transferase/transferase inhibitor
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PDB id
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4l02
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References listed in PDB file
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Key reference
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Title
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Structure guided design of a series of sphingosine kinase (sphk) inhibitors.
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Authors
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D.J.Gustin,
Y.Li,
M.L.Brown,
X.Min,
M.J.Schmitt,
M.Wanska,
X.Wang,
R.Connors,
S.Johnstone,
M.Cardozo,
A.C.Cheng,
S.Jeffries,
B.Franks,
S.Li,
S.Shen,
M.Wong,
H.Wesche,
G.Xu,
T.J.Carlson,
M.Plant,
K.Morgenstern,
K.Rex,
J.Schmitt,
A.Coxon,
N.Walker,
F.Kayser,
Z.Wang.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
4608-4616.
[DOI no: ]
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PubMed id
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Abstract
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Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell
migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in
sphingomyelin metabolism that leads to the production of S1P. There are two
isoforms of SphK and observations made with SphK deficient mice show the two
isoforms can compensate for each other's loss. Thus, inhibition of both isoforms
is likely required to block SphK dependent angiogenesis. A structure based
approach was used to design and synthesize a series of SphK inhibitors resulting
in the identification of the first potent inhibitors of both isoforms of human
SphK. Additionally, to our knowledge, this series of inhibitors contains the
only sufficiently potent inhibitors of murine SphK1 with suitable
physico-chemical properties to pharmacologically interrogate the role of SphK1
in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
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