This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhu, M. Articles by Han, H. Search for Related Content PubMed PubMed Citation Articles by Zhu, M. Articles by Han, H.

Research Articles: Therapeutics, Targets, and Development

Identification of a novel inhibitor of urokinase-type plasminogen activator

¹ Division of Clinical Translational Research, Translational Genomics Research Institute, Phoenix, Arizona and ² College of Pharmacy, Arizona Cancer Center and BIO5 Institute, The University of Arizona, Tucson, Arizona

Requests for reprints: Haiyong Han, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004. Phone: 602-343-8739; Fax: 602-343-8740. E-mail: hhan{at}tgen.org

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, UK122, showed the highest inhibition of uPA activity. The IC₅₀ of UK122 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. [Mol Cancer Ther 2007;6(4):1348–56]

Grant support: National Foundation for Cancer Research (D.D. Von Hoff and L.H. Hurley).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/25/06; revised 12/27/06; accepted 2/26/07.