Home Blog of Signal Transduction PI3K/Akt/mTOR Akt Azeliragon inhibits PAK1 and enhances the therapeutic efficacy of AKT inhibitors in pancreatic cancer

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Azeliragon inhibits PAK1 and enhances the therapeutic efficacy of AKT inhibitors in pancreatic cancer

Pancreatic cancer is a lethal malignancy for which there is currently no effective treatment strategy. We previously reported that p21-activated kinase 1 (PAK1) is aberrantly expressed in pancreatic cancer patients and that targeted inhibition of PAK1 significantly suppressed pancreatic cancer progression in vitro and in vivo. In this study, we identified the drug azeliragon as a novel inhibitor of PAK1. Cell experiments revealed that azeliragon abolished PAK1 activation and promoted apoptosis in pancreatic cancer cells. Azeliragon was also found to significantly inhibit tumor growth in a pancreatic cancer xenograft model; when combined with afuresertib, an oral pan-AKT kinase inhibitor, azeliragon exhibited a strong synergistic effect against pancreatic cancer cells. Interestingly, afuresertib enhanced the antitumor efficacy of azeliragon in a xenograft mouse model. Collectively, our findings revealed previously unreported aspects of the drug azeliragon, and identified a novel combination strategy for the treatment of pancreatic cancer patients.

 

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The study suggests that PAK1, an aberrantly expressed protein in pancreatic cancer, could be targeted for treatment. Through cell experiments, you demonstrated that azeliragon effectively suppressed PAK1 activation and induced apoptosis in pancreatic cancer cells. Additionally, in a pancreatic cancer xenograft model, azeliragon significantly inhibited tumor growth.

Furthermore, when azeliragon was combined with afuresertib, an oral pan-AKT kinase inhibitor, a strong synergistic effect against pancreatic cancer cells was observed. Remarkably, in a xenograft mouse model, afuresertib enhanced the antitumor efficacy of azeliragon. These findings provide new insights into the potential of azeliragon as a therapeutic drug and propose a novel combination strategy for the treatment of pancreatic cancer patients.

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S7521 Afuresertib (GSK2110183) Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively. Phase 2.

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