1vj9: Difference between revisions
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|PDB= 1vj9 |SIZE=350|CAPTION= <scene name='initialview01'>1vj9</scene>, resolution 2.4Å | |PDB= 1vj9 |SIZE=350|CAPTION= <scene name='initialview01'>1vj9</scene>, resolution 2.4Å | ||
|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=5IN:N-(BENZYLSULFONYL)-L-SERYL-N~1~-{4-[AMINO(IMINO)METHYL]BENZYL}-O-BENZYL-L-SERINAMIDE'>5IN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1f5k|1F5K]], [[1f5l|1F5L]], [[1f92|1F92]], [[1vja|1VJA]], [[1sc8|1SC8]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1vj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vj9 OCA], [http://www.ebi.ac.uk/pdbsum/1vj9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1vj9 RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
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 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Stuerzebecher, J.]] | [[Category: Stuerzebecher, J.]] | ||
[[Category: Zeslawska, E.]] | [[Category: Zeslawska, E.]] | ||
[[Category: human]] | [[Category: human]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
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[[Category: urokinase]] | [[Category: urokinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:25:13 2008'' | ||
Revision as of 00:25, 31 March 2008
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| , resolution 2.4Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | U-plasminogen activator, with EC number 3.4.21.73 | ||||||
| Related: | 1F5K, 1F5L, 1F92, 1VJA, 1SC8
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Urokinase Plasminogen Activator B-Chain-JT464 Complex
OverviewOverview
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.
About this StructureAbout this Structure
1VJ9 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents., Schweinitz A, Steinmetzer T, Banke IJ, Arlt MJ, Sturzebecher A, Schuster O, Geissler A, Giersiefen H, Zeslawska E, Jacob U, Kruger A, Sturzebecher J, J Biol Chem. 2004 Aug 6;279(32):33613-22. Epub 2004 May 18. PMID:15150279
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