title: Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents.
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.
authors.affiliation: Curacyte Chemistry GmbH, Winzerlaer Strasse 2, D-07745 Jena, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Ingo J
authors.initials: IJ
authors.lastname: Banke
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Anne
authors.initials: A
authors.lastname: Stürzebecher
authors.forename: Oliver
authors.initials: O
authors.lastname: Schuster
authors.forename: Andreas
authors.initials: A
authors.lastname: Geissler
authors.forename: Helmut
authors.initials: H
authors.lastname: Giersiefen
authors.forename: Ewa
authors.initials: E
authors.lastname: Zeslawska
authors.forename: Uwe
authors.initials: U
authors.lastname: Jacob
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001550:Benzamidines / Q000737:chemistry; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D005354:Fibrosarcoma; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D001550:Benzamidines; D004791:Enzyme Inhibitors; D014568:Urokinase-Type Plasminogen Activator