Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective
Inhibitors of Matriptase†
Posted on 2006-07-13 - 00:00
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 Ki 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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Steinmetzer, Torsten; Schweinitz, Andrea; Stürzebecher, Anne; Dönnecke, Daniel; Uhland, Kerstin; Schuster, Oliver; et al. (2016). Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective
Inhibitors of Matriptase†. ACS Publications. Collection. https://doi.org/10.1021/jm051272l
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AUTHORS (12)
TS
Torsten Steinmetzer
AS
Andrea Schweinitz
AS
Anne Stürzebecher
DD
Daniel Dönnecke
KU
Kerstin Uhland
OS
Oliver Schuster
PS
Peter Steinmetzer
FM
Friedemann Müller
RF
Rainer Friedrich
MT
Manuel E. Than
WB
Wolfram Bode
JS
Jörg Stürzebecher