Abstract Number: PB1467
Meeting: ISTH 2020 Congress
Background: Ischaemic heart disease and stroke have been the two major causes of death worldwide. As platelets play an essential role in the development and progression of these cardiovascular diseases, antiplatelet agents represent the treatment of choice in these patients. Glycoprotein VI (GPVI) is the major collagen receptor in platelets and has been proposed as a promising therapeutic because of their essential role in thrombosis while it is not critically required for haemostasis.
Aims: The main goal of the present study was to identify novel antiplatelet agent targeting GPVI signalling.
Methods: We performed a high-throughput screening (HTS) assay measuring intracellular calcium mobilization in real time upon platelet activation with the GPVI-specific agonist collagen-related peptide (CRP). Published Kinase Inhibitors Set (PKIS) library developed through drug discovery efforts by GSK was screened. Inhibitors showing activity were then tested by a series of thrombosis and haemostasis relevant in-vitro and in-vivo assays.
Results: Phosphoinositide 3-kinase (PI3K) selective inhibitor of P110δ isoform drug Idelalisib was identified as a hit that potently blocks intracellular calcium release, with an EC50 of 1.3µM. We also demonstrated that Idelalisib efficiently blocks CRP-induced aggregation whereas collagen-induced aggregation is also moderately inhibited without significant effects in platelet viability. Moreover, platelet adhesion to collagen was highly reduced when platelets were preincubated with the inhibitor. To further investigate the potential of the inhibitor as antithrombotic, in-vivo assays using a ferric chloride-induced arterial thrombosis animal model were carried out. The results revealed that the occlusion time was significantly reduced when mice were treated with Idelalisib at 20mg/kg (Figure 1).
Conclusions: The Idelalisib block effectively and selectively GPVI-induced platelet activation and shows antithrombotic potential in vivo. Further confirmation of the preclinical efficacy at platelet aggregation as well as better understanding of GPVI-related the mechanism of action might support the repurposing of these drug as antiplatelet agent.
To cite this abstract in AMA style:Nuñez Barrachina M, Izquierdo I, Hermida-Nogueira L, Morán LA, Arroyo AB, García-Barberá N, González-Conejero R, Rivera J, Martínez C, Loza MI, Domínguez E, García Á. Idelalisib Selectively Inhibits GPVI-mediated Platelet Activation and Shows Anti-atherothrombotic Activity [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/idelalisib-selectively-inhibits-gpvi-mediated-platelet-activation-and-shows-anti-atherothrombotic-activity/. Accessed February 20, 2024.
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