ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

Kyungho Kim, Jing Li, Andrew Barazia, Alan Tseng, Seock Won Youn, Giovanni Abbadessa, Yi Yu, Brian Schwartz, Robert K. Andrews, Victor R. Gordeuk, Jaehyung Cho

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50-500 nM ARQ 092 significantly blocks M2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-. Coadministration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vasoocclusive complications in patients with sickle cell disease.

Original languageEnglish (US)
Pages (from-to)246-259
Number of pages14
JournalHaematologica
Volume102
Issue number2
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease'. Together they form a unique fingerprint.

  • Cite this

    Kim, K., Li, J., Barazia, A., Tseng, A., Youn, S. W., Abbadessa, G., Yu, Y., Schwartz, B., Andrews, R. K., Gordeuk, V. R., & Cho, J. (2017). ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease. Haematologica, 102(2), 246-259. https://doi.org/10.3324/haematol.2016.151159