Targeting a novel anti-platelet mechanism for improved anti-thrombotic therapy

Project: Research

Project Description

Arterial thrombosis causes heart attacks and most strokes and is the most common cause of death in the world. Platelets are the cells that form arterial thrombi, and anti-platelet drugs are the mainstay of heart attack and stroke prevention. Yet current drugs have limited efficacy – preventing fewer than 25% of lethal cardiovascular events without clinically significant effects on bleeding. As a result, there is a major need for improved therapies. The key limitation on the ability of all current drugs to impair thrombosis without causing bleeding is that they all target agonist-dependent platelet activation mechanisms, thereby non-specifically preventing platelet function. We have recently identified an approach that overcomes this limitation by preventing platelet function specifically in the setting of thrombosis and independently of agonist-dependent platelet activation. Specifically, PI3KC2α-deficient mice are protected from arterial thrombosis but do not bleed. Remarkably, this anti-thrombotic effect occurred independently of effects on platelet activation. Rather, PI3KC2α-deficient platelets had an altered structure of their internal membrane reserves that led to impaired adhesion specifically in the setting of thrombosis, suggesting a mechanism distinct from all other known anti-platelet approaches. Here, we will develop the first PI3KC2α inhibitors and use them to translate our findings to humans. Initial work has produced a suite of compounds with varying levels of activity and selectivity. Preliminary experiments reveal that only compounds with activity against PI3KC2α reproduce the unique phenotype observed in PI3KC2α-deficient mice, indicating the important function of PI3KC2α in platelets is conserved in humans. Based on these strong founding studies, we now propose to:
1) Develop specific inhibitors of PI3KC2α.
2) Determine the anti-thrombotic effects of PI3KC2α inhibition.
3) Define the mechanism by which PI3KCα inhibition prevents thrombosis.
StatusActive
Effective start/end date1/01/1831/12/21

Funding

  • National Health & Medical Research Council (NHMRC): AUD985,938.00