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Design and Synthesis of Potent, Selective Inhibitors of Matriptase

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journal contribution
posted on 12.07.2012, 00:00 by Éloïc Colombo, Antoine Désilets, Dominic Duchêne, Félix Chagnon, Rafael Najmanovich, Richard Leduc, Eric Marsault
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.