Biological Activity
gne-317 is a potent inhibitor of pi3k [1].phosphatidylinositol-4,5-bisphosphate 3-kinase (pi3k) are a series of enzymes and play an important role in cell growth, proliferation, differentiation, survival, motility and intracellular trafficking.in the gl261 cell line, gne-317 showed cytotoxic activity [2].in mouse brain, gne-317(50 mg/kg) significantly inhibited pakt, p4ebp1 and ps6 by 80%, 84%, and 92% respectively, which were downstream markers of the pi3k/mtor pathway. in u87, gs2 and gbm10 tumor-bearing mice, gne-317 inhibited tumor growth by 90%, 50% and a survival benefit, respectively [1]. in c57b6/j mice inoculated with gl261-gfp-luc cells, the concentrations of gne-317 in the normal brain, tumor core and rim were not significantly different. in tumor-bearing mice, gne-317 significantly reduced the levels of p-aktser473, p-s6ser235/236 and p-4ebp1thr37/46 within the tumor [2]. in u87 and gs2 glioblastoma multiforme (gbm) models, gne-317 was uniformly distributed in the brain. the brain-to-plasma ratios for gne-317 were greater than 1, in agreement with the brain penetration properties of gne-317 [3].
in vitro
GNE-317 is not a substrate of P-gp or BCRP transporter in transfected Madin-Darby canine kidney (MDCK) cells. Binding of it 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%.It shows cytostasis but no cell death to U87 cells.
in vivo
GNE-317 (40 mg/kg, po) 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, po) ) is ef?cacious 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, po; 40 mg/kg the ?rst 2 weeks) extends the survival of mice from a median of 55.5 to 75 days.
