Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier

Clin Cancer Res. 2012 Nov 15;18(22):6239-48. doi: 10.1158/1078-0432.CCR-12-0720. Epub 2012 Sep 19.


Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM.

Experimental design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM.

Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively.

Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / pathology
  • Capillary Permeability
  • Cell Line
  • Cell Membrane Permeability
  • Dogs
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology
  • Thiophenes / pharmacokinetics*
  • Thiophenes / pharmacology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • GNE-317
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiophenes
  • Proto-Oncogene Proteins c-akt