ArticleHaematologica2017
ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease.
Article in Haematologica, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Beneficial effects of SGLT1/2 and SGLT2 inhibitors on vaso-occlusive events and organ damage in sickle cell disease mice.Cardiovascular research · 2026Article
- Pharmacological inhibition of Septins with Forchlorfenuron attenuates thrombus formation in experimental thrombotic mice models with modulating multiple signaling pathways in platelets.Journal of advanced research · 2025Article
- Human vascular organoids with a mosaicbioRxiv : the preprint server for biology · 2024Article
- Mechanism of Tao Hong Decoction in the treatment of atherosclerosis based on network pharmacology and experimental validation.Frontiers in cardiovascular medicine · 2023Article
- Role of protein phosphorylation in cell signaling, disease, and the intervention therapy.MedComm · 2022Review
- Increased platelet thrombus formation under flow conditions in whole blood from polycythaemia vera patients.Blood transfusion = Trasfusione del sangue · 2022Article
- Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation.The Journal of experimental medicine · 2022Article
- Sickle cell vaso-occlusion: The dialectic between red cells and white cells.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review.Medical oncology (Northwood, London, England) · 2021Review
- Complement in Sickle Cell Disease: Are We Ready for Prime Time?Journal of blood medicine · 2021Review
- Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance.Haematologica · 2020Article
- Innate immune cells, major protagonists of sickle cell disease pathophysiology.Haematologica · 2020Review
- Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2-PKC-AKT Activation in Human Platelets.International journal of molecular sciences · 2019Article
- Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ibα-Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions.Circulation · 2019Article
- Targeting allosteric site of AKT by 5,7-dimethoxy-1,4-phenanthrenequinone suppresses neutrophilic inflammation.EBioMedicine · 2019Article
- The Akt pathway in oncology therapy and beyond (Review).International journal of oncology · 2018Review
- Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma.Oncotarget · 2018Article
- Myeloperoxidase Negatively Regulates Neutrophil-Endothelial Cell Interactions by Impairing αMβ2 Integrin Function in Sterile Inflammation.Frontiers in medicine · 2018Article
- Article
- Ser/Thr protein kinase Bβ-NADPH oxidase 2 signaling in thromboinflammation.Current opinion in hematology · 2017Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
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