1VJ9

Urokinase Plasminogen Activator B-Chain-JT464 Complex

Summary for 1VJ9

• Entry DOI: 10.2210/pdb1vj9/pdb
• Related: 1F5K 1F5L 1F92 1SC8 1VJA
• Descriptor: plasminogen activator, urokinase, SULFATE ION, N-(BENZYLSULFONYL)-L-SERYL-N~1~-{4-[AMINO(IMINO)METHYL]BENZYL}-O-BENZYL-L-SERINAMIDE, ... (4 entities in total)
• Functional Keywords: urokinase, inhibitor, serine protease, human, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00749
• Total number of polymer chains: 1
• Total formula weight: 30443.73

Authors

Schweinitz, A.,Steinmetzer, T.,Banke, I.J.,Arlt, M.J.E.,Stuerzebecher, A.,Schuster, O.,Geissler, A.,Giersiefen, H.,Zeslawska, E.,Jacob, U.,Kruger, A.,Stuerzebecher, J. (deposition date: 2004-02-03, release date: 2004-06-22, Last modification date: 2024-11-20)

Primary citation

Schweinitz, A.,Steinmetzer, T.,Banke, I.J.,Arlt, M.J.E.,Stuerzebecher, A.,Schuster, O.,Geissler, A.,Giersiefen, H.,Zeslawska, E.,Jacob, U.,Kruger, A.,Stuerzebecher, J.
Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents
J.Biol.Chem., 279:33613-33622, 2004

PubMed Abstract: 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.

PubMed: 15150279
DOI: 10.1074/jbc.M314151200

Experimental method

X-RAY DIFFRACTION (2.4 Å)