Design and synthesis of potent, selective inhibitors of matriptase.

Abstract

Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.

• Authors: Eloïc Colombo, Antoine Désilets, Dominic Duchêne, Félix Chagnon, Rafael Najmanovich, Richard Leduc, Eric Marsault
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 7 Pg. 530-4 (Jul 12 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900505 (Publication Type: Journal Article)