As a trypsin-like serine protease, Urokinase-type plasminogen activator （uPA） plays a key role in a range of biological processes including plasminogen activation, angiogenesis, wound healing, tissue remodeling, tum...As a trypsin-like serine protease, Urokinase-type plasminogen activator （uPA） plays a key role in a range of biological processes including plasminogen activation, angiogenesis, wound healing, tissue remodeling, tumor growth and tumor metastasis, uPA is shown as the most validated marker for prognosis of breast cancer. Inhibitors of uPA may then be useful in the treatment of cancer by retarding tumor growth and metastasis. Most current uPA inhibitors employ a highly basic group （amidine or guanidine group） to target the primary specific pocket of uPA active site, which leads to poor oral bioavailability. Here, a uPA inhibitor with weak basic P1 group, 2-（2-amino- benzothiazole-6-carboxamido）acetic acid （ABTCA）, was synthesized and reported here. In addition, we also determined the crystal structure of ABTCA in complex with uPA. The structural information will be useful for further improvements of potency and selectivity of this promising new type ofuPA inhibitors.展开更多
基金supported by the National Natural Foundation of China (No.31161130356)Foundation of Fujian Provincial Education Department (No.JA11020)Foundation of Fuzhou University (No.2010-XQ-06)
文摘As a trypsin-like serine protease, Urokinase-type plasminogen activator （uPA） plays a key role in a range of biological processes including plasminogen activation, angiogenesis, wound healing, tissue remodeling, tumor growth and tumor metastasis, uPA is shown as the most validated marker for prognosis of breast cancer. Inhibitors of uPA may then be useful in the treatment of cancer by retarding tumor growth and metastasis. Most current uPA inhibitors employ a highly basic group （amidine or guanidine group） to target the primary specific pocket of uPA active site, which leads to poor oral bioavailability. Here, a uPA inhibitor with weak basic P1 group, 2-（2-amino- benzothiazole-6-carboxamido）acetic acid （ABTCA）, was synthesized and reported here. In addition, we also determined the crystal structure of ABTCA in complex with uPA. The structural information will be useful for further improvements of potency and selectivity of this promising new type ofuPA inhibitors.
