The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Abstract

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.

Novel Targets for Old and Diseased Hearts

“…More concrete evidence of novel targets to be exploited therapeutically for vascular disorders are provided by two additional works that focus on two major pathogenetic mechanisms of vessel disease, namely thrombosis and arterial restenosis [ 5 ].…”

“…Available drugs able to interfere with platelet aggregation are associated with increased risk of hemorrhage, warranting the development of effective, yet safer, anti-platelet drugs. The work by Barrachina et al has identified a compound, called Idelalisib, which potently inhibits platelet adhesion and aggregation by blocking Phosphoinositide 3-kinases (PI3K), but shows minimal bleeding effects in mice, compared to standard anti-platelet therapy, such as aspirin and clopidogrel, in mouse models [ 5 , 6 ].…”