The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

  • Int J Mol Sci. 2021 Mar 24;22(7):3304. doi: 10.3390/ijms22073304.
María N Barrachina  1 ,  Irene Izquierdo  1 ,  Lidia Hermida-Nogueira  1 ,  Luis A Morán  1 ,  Amparo Pérez  2  3 ,  Ana B Arroyo  4 ,  Nuria García-Barberá  4 ,  Rocío González-Conejero  4 ,  Sara Troitiño  1 ,  Johannes A Eble  5 ,  José Rivera  4 ,  Constantino Martínez  4 ,  María I Loza  2  3 ,  Eduardo Domínguez  2  3 ,  Ángel García  1
Affiliations
  • 1. Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases, Universidade Santiago de Compostela and Instituto de Investigación Sanitaria de Santiago, 15706 Santiago de Compostela, Spain.
  • 2. Pharmacology Applied to Drug Discovery Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidade Santiago de Compostela, 15705 Santiago de Compostela, Spain.
  • 3. Grupo Biofarma, Instituto de Investigación Sanitaria de Santiago, 15706 Santiago de Compostela, Spain.
  • 4. Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, 30003 Murcia, Spain.
  • 5. Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
PMID: 33804911 DOI: 10.3390/ijms22073304
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.

Keywords
Idelalisib; PI3K inhibitors; platelets.
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