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PDBsum entry 2gv7
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References listed in PDB file
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Key reference
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Title
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Secondary amides of sulfonylated 3-Amidinophenylalanine. New potent and selective inhibitors of matriptase.
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Authors
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T.Steinmetzer,
A.Schweinitz,
A.Stürzebecher,
D.Dönnecke,
K.Uhland,
O.Schuster,
P.Steinmetzer,
F.Müller,
R.Friedrich,
M.E.Than,
W.Bode,
J.Stürzebecher.
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Ref.
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J Med Chem, 2006,
49,
4116-4126.
[DOI no: ]
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PubMed id
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Abstract
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Matriptase is an epithelium-derived type II transmembrane serine protease and
has been implicated in the activation of substrates such as pro-HGF/SF and
pro-uPA, which are likely involved in tumor progression and metastasis. Through
screening, we have identified bis-basic secondary amides of sulfonylated
3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8
and 31 in complex with matriptase revealed that these inhibitors occupy, in
addition to part of the previously described S4-binding site, the cleft formed
by the molecular surface and the unique 60 loop of matriptase. Therefore,
optimization of the inhibitors included the incorporation of appropriate
sulfonyl substituents that could improve binding of these inhibitors into both
characteristic matriptase subsites. The most potent derivatives inhibit
matriptase highly selective with K(i) values below 5 nM. Molecular modeling
revealed that their improved affinity results from interaction with the S4 site
of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse
model of prostate cancer. Compared to control, both inhibitors reduced tumor
growth, as well as tumor dissemination.
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