Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922)

•Potent and selective inhibitors of PI3Kβ.•Distinct mechanisms underpinning selectivity compared to known inhibitors.•Anti-platelet activity shown in platelet aggregation, activation and adhesion in vitro.•Anti-thrombotic activity in vivo in mouse electrolytic injury model without effects on haemostasis.

A series of amino-substituted triazines were developed and examined for PI3Kβ inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kβ selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3Kβ selective inhibitor from the series was studied in detail through a series of in vitro and in vivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin αIIbβ3 activation and αIIbβ3 dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the in vivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide