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Targeting proteases in cancer: Discovery of a novel zymogen targeting inhibitor of urokinase-type plasminogen activator

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Urokinase-type plasminogen activator (uPA) is a potential therapeutic target in cancer. Yet, classical development of small molecule inhibitors of uPA has proved a daunting task, with only limited success in engineering high affinity and specificity among related proteases having conserved active site architecture In nature, a key mechanism of protease regulation is the point of zymogen activation. Thus far, controlling protease activity by targeting the zymogen activation step is an underexploited strategy. We have now designed a specific monoclonal antibody inhibitor (Mab-112) with sub-nanomolar affinity to pro-uPA. A detailed mechanistic evaluation with several biophysical methods and alanine-scanning mutagenesis elucidated a novel multifunctional mechanism whereby Mab-112 by binding to the activation domain retards the proteolytic conversion of single-chain pro-uPA into the two-chain form and subsequently averts the conformational transition to a mature protease by sequestering the two-chain form in a zymogen-like state. Furthermore, Mab-112 is a non-competitive inhibitor of two-chain uPA, stabilising the protease in a non-catalytic conformation. Functional studies employing high intravasating (HT-hi/diss) and low intravasating (HT-lo/diss) variants of the human HT-1080 cell line demonstrate that Mab-112 is an effective inhibitor of intravasation in the chorioallantoic membrane assay. These findings show the utility of pharmacological interference of zymogen activation as a plausible and robust means to regulate uPA activity and the downstream effects of plasminogen activation. Furthermore, a strategy that targets regions related to pro-enzyme activation likely provide a unique inhibitor-protease interaction surface and is thus expected to enhance the chances of engineering high inhibitor specificity.

Document Type: Abstract


Affiliations: 1: Molekylærbiologisk Institut, Aarrhus Univertsitet, Gustav Wieds Vej 10C, 8000 Aarhus C 2: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

Publication date: May 1, 2008


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