Abstract 3752: Nanoparticles delivery of a novel AKT/PDK1 inhibitor inhibits pancreatic cancer tumor growth

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.3752-3752
• Main Authors: Meuillet, Emmanuelle J., Moses, Sylvestor A., Lucero-Acuna, Armando, Guzman, Roberto, Jeffrey, Justin, Pagel, Mary
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3752

AKT (protein kinase B), a pleckstrin homology (PH) lipid binding domain and a serine/threonine kinase containing protein is a key component of the phophatidylinositol-3-kinase (PtdIns3-K) cell survival signaling pathway which is activated in pancreatic cancers. In this study, we describe the effects of a novel inhibitor of AKT/PDK1 (PH-427) that binds to the PH domain of AKT (Ki = 2.67 ± 0.37 μM) and PDK1 (Ki = 5.20 ± 0.45 μM) [1] thus preventing its binding to PtIns-(3,4,5)P3 at the plasma membrane and subsequent activation of both kinases. PH-427 inhibits AKT/PDK1 activities at low micromolar concentrations in BxPC-3 (wt-KRAS) and not in MiaPaCa2 (mt-KRAS) human pancreatic cancer cell lines. Accordingly, we have shown that in vivo, PH-427 is poorly efficient in MiaPaCa2 xenografts as compared to BxPC-3 xenografts. In order to increase the potency and delivery of PH-427 to the tumor, we have encapsulated the compound (>10% of the compound) into (poly-d, l-lactide-co-glycolide) (PLGA) nanoparticles (PNP). We demonstrate that PH-427 incorporates well in the nanoparticles (PH-427-PNP) (