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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.

SUBMITTER: Colombo E

PROVIDER: S-EPMC4025795 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Design and synthesis of potent, selective inhibitors of matriptase.

Colombo Eloïc E Désilets Antoine A Duchêne Dominic D Chagnon Félix F Najmanovich Rafael R Leduc Richard R Marsault Eric E

ACS medicinal chemistry letters 20120411 7

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-p ...[more]

PMID: 24900505

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