LeadDiscovery has recently produced a series of DiscoveryDossiers for the exciting cardiovascular-focused company, ThromboGenics (click here for access). This company has targeted a number of highly novel and effective approaches for the improved treatment of cardiovascular diseases as well as those involving altered angiogenesis. A number of their programs are designed to develop thrombolytics devoid of hemorrhagic side effects. Plasminogen, a central component of the thrombolytic pathway, is activated through its conversion to plasmin, which serves to digest fibrin in blood clots. Plasminogen activation is under the control of t-PA and urokinase. Recombinant forms of both enzymes have been developed for therapeutic use. Urokinase and early forms of t-PA both cause significant bleeding and the separation of these two events has represented a key target. Various forms of improved t-PA such as Reteplase and Tenecteplase have thus been developed. Streptokinase is a thrombolytic that is also in common use. This 414-residue protein secreted by hemolytic strains of Streptococci facilitates the activation plasminogen, however once again it is associated with a significant incidence of hemorrhage. Thus ThromboGenics is developing a variant of staphyolokinase (SY-161), a molecule completely unrelated to streptokinase, but which has the potential to replace this classic thrombolytic. Urokinase has been used therapeutically however it has since been withdrawn from the market. Prourokinase is a new fibrinolytic agent that is currently undergoing clinical trials by Abbott for a variety of indications including cerebral ischemia and peripheral arterial occlusive disease. It is a relatively inactive precursor of urokinase that must be converted to urokinase before it becomes active in vivo. Although prourokinase is quite stable in the plasma, it is prone to spontaneous cell-associated activation especially on the surface of endothelial cells that have previously bound kallikrein. Consequently therapeutic use of prourokinase risks the development of hemorrhage and has to date been limited to catheter delivery. Harvard researchers have now developed a mutant of prourokinase with even greater plasma stability and which causes faster plasminogen activation and greater fibrin-specific clot lysis than wild form prourokinase. Consequently this mutant produced more rapid and efficient clot lysis in dogs with no significant increase in the primary bleeding time or secondary bleeding. Prourokinase and tPA increased both of these parameters by 4-fold. Similar rapid clot lysis without a significant increase in the primary bleeding time, and secondary bleeding was observed in rhesus monkey. The therapeutic potential of this mutant form of prourokinase is thus considerable and its clinical development is eagerly awaited.

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