TY - JOUR
T1 - Identification of a novel inhibitor of urokinase-type plasminogen activator
AU - Zhu, Ming
AU - Gokhale, Vijay M.
AU - Szabo, Lajos
AU - Munoz, Ruben M.
AU - Baek, Hyounggee
AU - Bashyam, Sridevi
AU - Hurley, Laurence H.
AU - Von Hoff, Daniel D.
AU - Han, Haiyong
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-06-0520
DO - 10.1158/1535-7163.MCT-06-0520
M3 - Article
C2 - 17431113
AN - SCOPUS:34248189716
SN - 1535-7163
VL - 6
SP - 1348
EP - 1356
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 4
ER -