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Expert Opinion on Therapeutic Patents Volume 13, 2003 - Issue 6
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Review

Small molecule inhibitors of urokinase-type plasminogen activator

Todd W Rockway Abbott Laboratories, Global Pharmaceutical Research and Development, R47D, AP52N, 200 Abbott Park Road, Abbott Park, IL 60064-6217, USA. [email protected]
Pages 773-786 | Published online: 02 Mar 2005

Bibliography

  • NO AUTHORS LISTED: Cancer Facts and Figures. American Cancer Society Monograph (2002):1–45.
  • COUSSENS, LM, FINGLETON B, MATRISIAN LM: Matrix metalloprotease inhibitors and cancer: trials and tribulations. Science (2002) 295:2387–2392.
  • BEHRENDT N, RONNE E, PLOUG M et al.: The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants. " Biol. Chem. (1990) 265(11):6453–6460.
  • SCHMITT M, JANICKE F, MONIWA N eta.!.: Tumor-associated urokinase-type plasminogen activator: biological and clinical significance Biol. Chem. Hoppe Seyler (1992) 373(7):611–622.
  • DUFFY MJ: Plasminogen activators and cancer. Blood Coagul Fibrinolysis (1990) 1(6):681–687.
  • BUSSO N, SO A: Urokinase in rheumatoid arthritis: causal or coincidental? Ann. Rheum. Dis. (1997) 56(12):705–706.
  • RONDAY HK, SMITS HH, QUAX PH et al.: Bone matrix degradation by the plasminigen activation system. Possible mechanism of bone destruction in arthritis. Br.j Rheumatol (1997) 36:9–15.
  • CARMELIET P, MOONS L, LUNEN R et al: Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat. Cenetics(1997) 17(4):439–444.
  • NODA-HEINY H, DAUGHERTY A, SOBEL BE: Augmented urokinase receptor expression in atheroma. Arterioscler. Thromb. Vasc. Biol. (1995) 15(1):37–43.
  • HEYMANS S, LUTTUN A, NUYENS D: Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat. Med. (1999) 5(10):1135–1142.
  • REUNING U, MAGDOLEN V, WILHELM O et al.: Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis (review). hat. Oncology(1998) 13 (5):893–906.
  • EVANS DM, SLOAN-STAKLEFF K, ARVAN M, GUYTON DP: Time and dose dependency of the suppression of pulmonary metastasis of rat mammary cancer by amiloride. Clin. Exp. Metastasis (1998) 16:353–357.
  • BANERJI A, FERNANDES A, BANE S, AHIRE S: The field bean protease inhibitor has the potential to suppress B16F10 melanoma cell lung metastasis in mice. Cancer Lett. (1998) 129:15–20.
  • RABBANI SA, HARAKIDAS P, DAVIDSON DJ, HENKIN J, MAZAR AP: Prevention of prostate-cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator (uPA). Int. J. Cancer (1995) 63 (6):840–845.
  • ALONSO DF, TEJERA AM, FARIAS EF, BAL DE KIER JOFFE E, GOMEZ DE: Inhibition of mammary tumor cell adhesion, migration, and invasion by the selective synthetic urokinase inhibitor B428. Anti-Cancer Res. (1998) 18:4499–4504.
  • SHAPIRO RL, DUQUETTE JG, ROSES DFeta.!.: Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res. (1996) 56(15):3597–3604.
  • IGNAR DM, ANDREWS JL, WITHERSPOON SM et al: Inhibition of establishment of primary and micrometastatic tumors by a urokinase plasminogen activator receptor antagonist. Clin. Exp. Metastasis (1998) 16:9–20.
  • XING RH, RABBANI A: Ovemxpression of urokinase receptor in breast cancer cells results in increased tumor invasion, growth and metastasis. Int. Cancer (1996) 67:423–429.
  • MUELLER BM, YU YB, LAUG WE: Overexpression of plasminogen activator inhibitor 2 in human melanoma cells inhibits spontaneous metastasis in SCID/SCID mice. Proc. Natl. Acad. Sci. USA (1995) 92:205–209.
  • FOEKENS JA, BUESSECKER F, PETERS HA et al.: Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res. (1995) 55(7):1423–1427.
  • FLEISHER M: Prognostic markers other than hormone receptors in breast cancer. Clin. Ligand Assay (1998) 21:41–46.
  • GRONDAHL-HANSEN J, CHRISTENSEN IJ, BRIAND P et al.: Plasminogen activator inhibitor Type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients. Clin. Cancer Res. (1997) 3(2):233–239.
  • BAJOU K, NOEL A, GERARD RD eta.!.: Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat. Med. (1998) 4(8):923–928.
  • KIM SJ, SHIBA E, KOBAYASHI T et al: Prognostic impact of urokinase-type plasminogen activator (PA), PA inhibitor type-1, and tissue-type PA antigen levels in node-negative breast cancer: a prospective study on multicenter basis. Gin. Cancer Res. (1998) 4(1):177–182.
  • HARBECK N, DETTMAR P, THOMSSEN C et al: Prognostic impact of tumor biological factors on survival in node-negative breast cancer. Anti-Cancer Res. (1998) 18:2187–2198.
  • KWAAN HC, WANG J, SVOBODA K, DECLERCK PJ: Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br. Cancer (2000) 82:1702–1706.
  • MAZAR A, HENKIN J, GOLDFARB RH: The urokinase plasminogen activator system in cancer: implications for tumor angiogenesis and metastasis. Angiogenesis (1999) 3:15–32.
  • GRONDAHL-HANSEN J, CHRISTENSEN IJ, ROSENQUIST C et al.: High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. (1993) 53(11):2513–2521.
  • MAD, GERARD RD, LI XY, ALIZADEH H, NIEDERKORN JY: Inhibition of metastasis of intraocular melanomas by adenoviral gene transfer of plasminogen activator inhibitor Type 1 (PAI-1) in an athymic mouse model. Blood (1997) 90:2738–2746.
  • SOFF GA, SANDEROWITZ J, GATELY S et al.: Expression of plasminogen activator inhibitor Type 1 in human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis and metastasis to lung and liver in athymic mouse model." Gin. Invest. (1995) 96(6):2593–2600.
  • STEFANSSON S, LAWRENCE D: The serpin PAI-1 inhibits cell migration by blocking integrin ccI33 binding to vitronectin. Nat. Med. (1996) 383:441–443.
  • KJOLLER L, KANSE SM, KIRKEGAARD T et al.: Plasminogen activator inhibitor-1 represses integrin and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp. Cell Res. (1997) 232:420–429.
  • MCMAHON GA, PETITCLERC E, STEFANSSON S et al: Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J. Biol. Chem. (2001) 276(36):33964–33968.
  • PRAUS M, COLLEN D, GERARD RD: Both uPA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulates HT1080 fibrosarcoma cell metastasis. Int.' Cancer (2002) 102:584–591.
  • STEPHENS RW, BOKMAN AM, MYOHANEN HT et al.: Heparin binding to the urokinase kringle domain. Biochemistry (1992) 31(33):7572–7579.
  • HANSEN AP, PETROS AM, MEADOWS RP et al.: Solution structure of the amino-terminal fragment of urokinase-type plasminogen activator. Biochemistry (1994) 33(16):4847–4864.
  • BOKMAN AM, JIMENEZ-BARBERO J, LLINAS M: ['H]-NMR characterization of the urokinase kringle module. Structural, but not functional, relatedness to homologous domains.' Biol. Chem. (1993) 268(19):13858–13868.
  • LI X, BOKMAN AM, LLINAS M, SMITH RA, DOBSON CM: Solution structure of the kringle domain from urokinase-type plasminogen activator.' Mo/. Biol. (1994) 235(5):1548–1559.
  • KIM KS, HONG YK, JOE YA et al.: Anti-angiogenic activity of the recombinant kringle domain of urokinase and its specific entry into endothelial cells. " Biol. Chem. (2003) 278(13):11449–11456.
  • APPELLA E, ROBINSON EA, ULLRICH SJ et al.: The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. Biol. Chem. (1987) 262(10):4437–4440.
  • MAGDOLEN V, RETTENBERGER P, KOPPITZ M et al: Systematic mutational analysis of the receptor-binding region of the human urokinase-type plasminogen activator. Eur: Biochem. (1996) 237(3):743–751.
  • SCHMIEDEBERG N, SCHMITT M, ROLZ C et al: Synthesis, solution structure and biological evaluation of urokinase-type plasminogen activator (uPA)-derived receptor binding domain mimetics.j. Med. Chem. (2002) 45(23):4984–4994.
  • SPRAGGON G, PHILLIPS C, NOWAK UK et al.: The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure (1995) 3(7):681–691.
  • NIENABER V, WANG J, DAVIDSON D, HENKIN J: Re-engineering of human urokinase provides a system for structure-based drug design at high resolution and reveals a novel structural subsite. I Biol. Chem. (2000) 275(10):7239–7248.
  • NIENABER VL, DAVIDSON D, EDALJI R et al.: Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite. Structure (2000) 8(5):553–563.
  • NIENABER VL, RICHARDSON PL, KLIGHOFER V, BOUSKA JJ, GIRANDA VL, GREER J: Discovering novel figands for macromolecules using X-ray crystallographic screening. Nat. Biotechnol (2000) 18(101105–1108.
  • ZESLAWSKA E, SCHWEINITZ A, KARCHER A et al.: Crystals of the urokinase-type plasminogen activator variant 13 c-uPA in complex with small molecule inhibitors open the way towards structure-based drug design. " Mo/. Biol. (2000) 301:465–475.
  • GOODSON RJ, DOYLE MV, KAUFMAN SE, ROSENBERG S: High-affinity urokinase receptor antagonists identified with bacteriophage peptide display. Proc. Nat. Acad. Sci. USA (1994) 91(15):7129–7133.
  • PLOUG M, OSTERGAARD S, GARDSVOLL H et al.: Peptide derived antagonists of the urokinase receptor. Biochemistry (2001) 40(40):12157–12168.
  • MAGDOLEN V, BURGLE M, DE PRADA NA et al.: Cyclo19,31D-Cys191-uPA 19–31 is a potent competitive antagonist of the interaction of urokinase-type plasminogen activator with its receptor (CD87). Biol. Chem. (2001) 382(8):1197–205.
  • KE SH, COOMBS GS, TACHIAS K, COREY DR, MADISON EL: Optimal subsite occupancy and design of a selective inhibitor of urokinase. J. Biol. Chem. (1997) 272(33):20456–20462.
  • STURZEBECHER J, VIEWEG H, STEINMETZER T et al.: 3-Amidinophenylalanine-based inhibitors of urokinase. Bioorg. Med. Chem. Lett. (1999) 9(21):3147–3152.
  • SPENCER JR, MCGEE D, ALLEN D et at.: 4-Aminoarylguanidine and 4-aminobenzamidine derivatives as potent and selective urokinase-type plasminogen activator inhibitors. Bioorg. Med. Chem. Lett. (2002) 12(15):2023–2026.
  • MACKMAN RL, HUI HC, BREITENBUCHER JG et al.: 2- (2-Hydroxy-3-alkoxypheny0-1H-benzimidazole-5-carboxamidine derivatives as potent and selective urokinase-type plasminogen activator inhibitors. Bioorg. Med. Chem. Lett. (2002) 12(15):2019–2022.
  • WILSON KJ, ILLIG CR, SUBASINGHE N et al.: Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors. Bioorg. Med. Chem. Lett. (2001) 11(7):915–918.
  • RUDOLPH MJ, ILLIG CR, SUBASINGHE NL et al.: Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors. Bioorg. Med. Chem. Lett. (2002) 12(3):491–495.
  • TOWLE MJ, LEE A, MADUAKOR EC, SCHWARTZ CE, BRIDGES AJ, LITTLEFIELD BA: Inhibition of urokinase by 4-substituted benzo [b]thiophene-2-carboxamidines: an important new class of selective synthetic urokinase inhibitor. Cancer Res. (1993) 53(11):2553–2559.
  • NO AUTHORS LISTED: Selective urokinase inhibitors based on substituted aryl guanidines. Exp. Opin. Ther. Patents (2001) 11(12):1975–1977.
  • BARBER CG, DICKINSON RP: Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 2: (3-substituted-5-halo-2-pyridinyl)guanidines. Bioorg. Med. Chem. Lett. (2002) 12(2):185–187.
  • BARBER CG, DICKINSON RP, HORNE VA: Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 1: 2-pyridinylguanidines. Bioorg. Med. Chem. Letters (2002) 12(2):181–184

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