Identification of a novel inhibitor of urokinase-type plasminogen activator

Ming Zhu, Vijay Gokhale, Lajos Szabo, Ruben M. Munoz, Hyounggee Baek, Sridevi Bashyam, Laurence Hurley, Daniel D. Von Hoff, Haiyong Han

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Urokinase-type plasminogen activator (uPA), a highly restricted serine protease, plays an important role in the regulation of diverse physiologic and pathologic processes. Strong clinical and experimental evidence has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients. uPA has been considered as a promising molecular target for development of anticancer drugs. Here, we report the identification of several new uPA inhibitors using a high-throughput screen from a chemical library. From these uPA inhibitors, molecular modeling and docking studies identified 4-oxazolidinone as a novel lead pharmacophore. Optimization of the 4-oxazolidinone pharmacophore resulted in a series of structurally modified compounds with improved potency and selectivity. One of the 4-oxazolidinone analogues, UK 122, showed the highest inhibition of uPA activity. The IC50 of UK 122 in a cell-free indirect uPA assay is 0.2 μmol/L. This compound also showed no or little inhibition of other serine proteases such as thrombin, trypsin, plasmin, and the tissue-type plasminogen activator, indicating its high specificity against uPA. Moreover, UK122 showed little cytotoxicity against CFPAC-1 cells (IC50 > 100 μmol/L) but significantly inhibited the migration and invasion of this pancreatic cancer cell line. Our data show that UK122 could potentially be developed as a new anticancer agent that prevents the invasion and metastasis of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1348-1356
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number4
DOIs
StatePublished - Apr 2007

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Urokinase-Type Plasminogen Activator
Oxazolidinones
Plasminogen Inactivators
Serine Proteases
Pancreatic Neoplasms
Inhibitory Concentration 50
Small Molecule Libraries
Neoplasm Metastasis
Fibrinolysin
Tissue Plasminogen Activator
Pathologic Processes
Thrombin
Antineoplastic Agents
Trypsin
Cell Line
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Identification of a novel inhibitor of urokinase-type plasminogen activator. / Zhu, Ming; Gokhale, Vijay; Szabo, Lajos; Munoz, Ruben M.; Baek, Hyounggee; Bashyam, Sridevi; Hurley, Laurence; Von Hoff, Daniel D.; Han, Haiyong.

In: Molecular Cancer Therapeutics, Vol. 6, No. 4, 04.2007, p. 1348-1356.

Research output: Contribution to journalArticle

Zhu, Ming ; Gokhale, Vijay ; Szabo, Lajos ; Munoz, Ruben M. ; Baek, Hyounggee ; Bashyam, Sridevi ; Hurley, Laurence ; Von Hoff, Daniel D. ; Han, Haiyong. / Identification of a novel inhibitor of urokinase-type plasminogen activator. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 4. pp. 1348-1356.
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