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PDBsum entry 2gv7
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* Residue conservation analysis
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DOI no:
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J Med Chem
49:4116-4126
(2006)
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PubMed id:
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Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.
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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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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.Kotthaus,
T.Steinmetzer,
A.van de Locht,
and
B.Clement
(2011).
Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes).
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J Enzyme Inhib Med Chem,
26,
115-122.
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J.Napp,
C.Dullin,
F.Müller,
K.Uhland,
J.B.Petri,
A.van de Locht,
T.Steinmetzer,
and
F.Alves
(2010).
Time-domain in vivo near infrared fluorescence imaging for evaluation of matriptase as a potential target for the development of novel, inhibitor-based tumor therapies.
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Int J Cancer,
127,
1958-1974.
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K.A.Owen,
D.Qiu,
J.Alves,
A.M.Schumacher,
L.M.Kilpatrick,
J.Li,
J.L.Harris,
and
V.Ellis
(2010).
Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA.
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Biochem J,
426,
219-228.
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R.Ganesan,
C.Eigenbrot,
and
D.Kirchhofer
(2010).
Structural and mechanistic insight into how antibodies inhibit serine proteases.
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Biochem J,
430,
179-189.
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T.M.Antalis,
M.S.Buzza,
K.M.Hodge,
J.D.Hooper,
and
S.Netzel-Arnett
(2010).
The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment.
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Biochem J,
428,
325-346.
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S.Y.Choi,
S.Bertram,
I.Glowacka,
Y.W.Park,
and
S.Pöhlmann
(2009).
Type II transmembrane serine proteases in cancer and viral infections.
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Trends Mol Med,
15,
303-312.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
