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| [[Image:1vj9.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1vj9| PDB=1vj9 | SCENE= }} | | {{STRUCTURE_1vj9| PDB=1vj9 | SCENE= }} |
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| '''Urokinase Plasminogen Activator B-Chain-JT464 Complex'''
| | ===Urokinase Plasminogen Activator B-Chain-JT464 Complex=== |
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| ==Overview==
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| The serine protease urokinase-type plasminogen activator (uPA) interacts with a specific receptor (uPAR) on the surface of various cell types, including tumor cells, and plays a crucial role in pericellular proteolysis. High levels of uPA and uPAR often correlate with poor prognosis of cancer patients. Therefore, the specific inhibition of uPA with small molecule active-site inhibitors is one strategy to decrease the invasive and metastatic activity of tumor cells. We have developed a series of highly potent and selective uPA inhibitors with a C-terminal 4-amidinobenzylamide residue. Optimization was directed toward reducing the fast elimination from circulation that was observed with initial analogues. The x-ray structures of three inhibitor/uPA complexes have been solved and were used to improve the inhibition efficacy. One of the most potent and selective derivatives, benzylsulfonyl-D-Ser-Ser-4-amidinobenzylamide (inhibitor 26), inhibits uPA with a Ki of 20 nm. This inhibitor was used in a fibrosarcoma model in nude mice using lacZ-tagged human HT1080 cells, to prevent experimental lung metastasis formation. Compared with control (100%), an inhibitor dose of 2 x 1.5 mg/kg/day reduced the number of experimental metastases to 4.6 +/- 1%. Under these conditions inhibitor 26 also significantly prolonged survival. All mice from the control group died within 43 days after tumor cell inoculation, whereas 50% of mice from the inhibitor-treated group survived more than 117 days. This study demonstrates that the specific inhibition of uPA by these inhibitors may be a useful strategy for the treatment of cancer to prevent metastasis. | | The line below this paragraph, {{ABSTRACT_PUBMED_15150279}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15150279 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15150279}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Serine protease]] | | [[Category: Serine protease]] |
| [[Category: Urokinase]] | | [[Category: Urokinase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 12:35:34 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 00:50:37 2008'' |