Modulators of the urokinase-type plasminogen activation system for cancer

Abstract

The urokinase-type plasminogen activator (uPA) is a serine protease which acts as an initiator of extracellular matrix degradation and cell invasion. Urokinase acts with its cell surface receptor, uPAR, to promote cell adhesion, migration and invasion in co-operation with a number of other key molecular players, including plasminogen activator inhibitor-1 and integrins. Work in pharmaceutical and biotechnology companies has focused on the development of inhibitors of the urokinase enzyme activity and agents which prevent binding of uPA to uPAR for treatment of cancer progression. The challenge with the former is to generate orally-bioavailable small molecule inhibitors of sufficient selectivity with respect to other members of the trypsin family of serine proteases, especially tissue-type plasminogen activator and Factor Xa. A total of 14 patents have been published in this area from nine different companies over the last three years. With respect to inhibitors of the uPA:uPAR interaction the challenges have been to identify small molecules with significant potency and appropriate physicochemical properties. Most of the activity in this area has been with peptidic inhibitors. Six different companies have disclosed a total of 13 patents in this area. There are no announced clinical candidates in this field to date, although given the number of companies involved, this is likely to change in the near future.

• angiogenesis
• integrins
• metastasis
• serine proteases
• urokinase
• urokinase receptor