In vitro: GNE-317 is not a substrate of P-gp or BCRP transporter in transfected Madin-Darby canine kidney (MDCK) cells. Binding of GNE-317 to plasma proteins exhibits a free fraction of 14.9 % in mouse plasma, and binding to brain tissues is higher, with a free fraction of 5.4%. GNE-317 shows cytostasis but no cell death to U87 cells.
In vivo: GNE-317 (40 mg/kg, p.o.) markedly inhibits the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 (40 mg/kg, p.o.) is efﬁcacious in the U87 and GS2 orthotopic models, achieving tumor growth inhibition of 90% and 50%, respectively. In the GBM10 tumor model, GNE-317 (30 mg/kg, p.o.; 40 mg/kg the ﬁrst 2 weeks) extends the survival of mice from a median of 55.5 to 75 days.
|Animal models||U87 and GS2 orthotopic tumor-bearing mice|
|Formulation||0.5% methylcellulose/0.2%Tween 80|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||47 mg/mL warmed in DMSO|
Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma.
Becker CM, et al. Neuro Oncol. 2015 Sep;17(9):1210-9. PMID: 25972455.
Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging.
Salphati L, et al. Drug Metab Dispos. 2014 Jul;42(7):1110-6. PMID: 24754926.
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