Jump to main content
Jump to site search

Issue 9, 2019
Previous Article Next Article

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

Author affiliations

Abstract

Matriptase and hepsin are type II transmembrane serine proteases (TTSPs). Along with related S1 trypsin like serine protease HGFA (hepatocyte growth factor activator), their unregulated proteolytic activity has been associated with cancer including tumor progression and metastasis. These three proteases have two substrates in common, hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), the ligands for MET and recepteur d'origine nantais (RON) receptor tyrosine kinases. Mechanism-based tetrapeptide and benzamidine inhibitors of these proteases have been shown to block HGF/MET and MSP/RON cancer cell signaling. Herein, we have rationally designed a new class of peptidomimetic hybrid small molecule piperidine carbamate dipeptide inhibitors comparable in potency to much larger tetrapeptides. We have identified multiple compounds which have potent activity against matriptase and hepsin and with excellent selectivity over the off-target serine proteases factor Xa and thrombin.

Graphical abstract: Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

Back to tab navigation

Supplementary files

Article information


Submitted
18 Apr 2019
Accepted
17 Jul 2019
First published
18 Jul 2019

Med. Chem. Commun., 2019,10, 1646-1655
Article type
Research Article

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

V. C. Damalanka, S. A. Wildman and J. W. Janetka, Med. Chem. Commun., 2019, 10, 1646
DOI: 10.1039/C9MD00234K

Search articles by author

Spotlight

Advertisements