Design and Synthesis of Potent, Selective Inhibitors of Matriptase

被引：58

作者：

Colombo, Eloic ^{[1
]}

Desilets, Antoine ^{[1
]}

Duchene, Dominic ^{[2
]}

Chagnon, Felix ^{[1
]}

Najmanovich, Rafael ^{[2
]}

Leduc, Richard ^{[1
]}

Marsault, Eric ^{[1
]}

机构：

[1] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Pharmacol, Sherbrooke, PQ J1H 5N4, Canada

[2] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Biochem, Sherbrooke, PQ J1H 5N4, Canada

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 07期

基金：

加拿大健康研究院;

关键词：

matriptase; type II transmembrane serine protease; slow tight-binding inhibitor; TRANSMEMBRANE SERINE-PROTEASE; AUTOSOMAL RECESSIVE ICHTHYOSIS; IDENTIFICATION; ACTIVATOR; MUTATION;

D O I：

10.1021/ml3000534

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：530 / 534

页数：5

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