GNE-317

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].

References:
[1].  Salphati L, Heffron TP, Alicke B, et al. Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clin Cancer Res, 2012, 18(22): 6239-6248.
[2].  Becker CM, Oberoi RK, McFarren SJ, et al. Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. Neuro Oncol, 2015, pii: nov081.
[3].  Salphati L, Shahidi-Latham S, Quiason C, et al. 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. Drug Metab Dispos, 2014, 42(7): 1110-1116.