title: ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease.
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 αMβ2 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-α. Co-administration 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 vaso-occlusive complications in patients with sickle cell disease.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Barazia
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Tseng
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbadessa
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Andrews
authors.affiliation: Section of Hematology/Oncology, University of Illinois College of Medicine, Chicago, IL, USA.|Comprehensive Sickle Cell Center, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA thromres@uic.edu.
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D015415:Biomarkers; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D015415:Biomarkers; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; C000608559:Miransertib; D006918:Hydroxyurea