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

Abstract

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.

• Authors: Weikang Kong, Lingxia Zhu, Tian Li, Jiao Chen, Bo Fan, Wenjing Ji, Chunli Zhang, Xueting Cai, Chunping Hu, Xiaoyan Sun, Peng Cao
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 948 Pg. 175703 (Jun 05 2023) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 37028543 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• afuresertib
• azeliragon
• Proto-Oncogene Proteins c-akt
• p21-Activated Kinases
• Protein Kinase Inhibitors
• PAK1 protein, human

Topics

• Humans
• Animals
• Mice
• Proto-Oncogene Proteins c-akt
• p21-Activated Kinases
• Cell Line, Tumor
• Pancreatic Neoplasms (drug therapy, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Cell Proliferation
• Xenograft Model Antitumor Assays