Discovery of Selective Matriptase and Hepsin Serine Protease Inhibitors: Useful Chemical Tools for Cancer Cell Biology

Matriptase and hepsin belong to the
family of type II transmembrane
serine proteases (TTSPs). Increased activity of these and the plasma
protease, hepatocyte growth factor activator (HGFA), is associated
with unregulated cell signaling and tumor progression through increased
MET and RON kinase signaling pathways. These proteases are highly
expressed in multiple solid tumors and hematological malignancies.
Herein, we detail the synthesis and structure–activity relationships
(SAR) of a dipeptide library bearing Arg α-ketobenozothiazole
(kbt) warheads as novel inhibitors of HGFA, matriptase, and hepsin.
We elucidated the substrate specificity for HGFA using positional
scanning of substrate combinatorial libraries (PS-SCL), which was
used to discover selective inhibitors of matriptase and hepsin. Using
these selective inhibitors, we have clarified the specific role of
hepsin in maintaining epithelial cell membrane integrity, known to
be lost in breast cancer progression. These selective compounds are
useful as chemical biology tools and for future drug discovery efforts.