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

Li, Jing; Barazia, Andrew; Tseng, Alan; Youn, Seock Won; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Andrews, Robert K.; Cho, Jaehyung

doi:10.3324/haematol.2016.151159

Cited by 24 publications

(26 citation statements)

References 48 publications

(91 reference statements)

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“…The strong reduction of circulating neutrophils in rats treated by ARQ 092 monotherapy should to be taken into account. In fact, ARQ 092 was recently used to block neutrophils and decrease inflammation in sickle cell disease [ 25 ]. However, because neutrophils are the first responders to sites of acute injury and infection, the effect of ARQ 092 on circulating neutrophils needs to be mentioned.…”

Section: Discussionmentioning

confidence: 99%

Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma

et al. 2018

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Copyright: Macek Jilkova et al. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTThe prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The AKT pathway is activated in almost half of HCC cases and in addition, long term exposure to conventional drug treatment of HCC, sorafenib, often results in overactivation of AKT, leading to HCC resistance. Therefore, it is important to assess the safety and the efficacy of selective allosteric AKT inhibitor ARQ 092 (Miransertib) in combination with sorafenib.Here, we demonstrated in vitro that the combination of ARQ 092 with sorafenib synergistically suppressed proliferation, promoted apoptosis, and reduced migration. To test the effect of the combination in vivo, rats with diethylnitrosamine-induced cirrhosis and fully developed HCC were randomized and treated with vehicle, sorafenib, ARQ 092 or the combination of ARQ 092 with sorafenib; (n=7/group) for 6 weeks. Tumor progression, size of tumors and the mean tumor number were significantly reduced by the combination treatment compared to the control or single treatments. This effect was associated with a significant increase in apoptotic response and reduction in proliferation and angiogenesis. Sirius red staining showed a decrease in liver fibrosis. Moreover, treatments improved immune response in blood and in tumor microenvironment.Thus, the combination of ARQ 092 with sorafenib potentiates inhibition of tumor progression and gives the possibility of therapeutic improvement for patients with advanced HCC.

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Section: Discussionmentioning

confidence: 99%

Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma

et al. 2018

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“…Miransertib (ARQ 092) binds to the inactive Akt and inhibits non-competitively all three isoforms at nanomolar concentrations and has excellent selectivity over other kinases ( 173 ). It is analyzed in several clinical trials for treatment as single therapy or combinations of advanced solid tumors and recurrent malignant lymphoma.…”

Section: Akt Inhibitors In Clinical Studiesmentioning

confidence: 99%

The Akt pathway in oncology therapy and beyond (Review)

et al. 2018

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Protein kinase B (Akt), similar to many other protein kinases, is at the crossroads of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and division, apoptosis suppression and angiogenesis. Akt protein kinase displays important metabolic effects, among which are glucose uptake in muscle and fat cells or the suppression of neuronal cell death. Disruptions in the Akt-regulated pathways are associated with cancer, diabetes, cardiovascular and neurological diseases. The regulation of the Akt signaling pathway renders Akt a valuable therapeutic target. The discovery process of Akt inhibitors using various strategies has led to the identification of inhibitors with great selectivity, low side-effects and toxicity. The usefulness of Akt emerges beyond cancer therapy and extends to other major diseases, such as diabetes, heart diseases, or neurodegeneration. This review presents key features of Akt structure and functions, and presents the progress of Akt inhibitors in regards to drug development, and their preclinical and clinical activity in regards to therapeutic efficacy and safety for patients.

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“…Eleni Gavriilaki,1 Maria Mainou, 2 Ioanna Christodoulou, 2 Eudoxia-Evaggelia Koravou, 1 Aggeliki Paleta, 1 Tasoula Touloumenidou, 1 Apostolia Papalexandri, 1 Anastasia Athanasiadou, 1…”

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confidence: 99%