GNE-317

• CAT Number: I001511
• CAS Number: 1394076-92-6
• Molecular Formula: C₁₉H₂₂N₆O₃S
• Molecular Weight: 414.48
• Purity: ≥95%
• Target: PI3K
• Solubility: DMSO: ≥ 20 mg/mL
• Storage: Store at -20°C
• InChI: InChI=1S/C19H22N6O3S/c1-11-13-14(29-15(11)19(26-2)9-28-10-19)17(25-3-5-27-6-4-25)24-16(23-13)12-7-21-18(20)22-8-12/h7-8H,3-6,9-10H2,1-2H3,(H2,20,21,22)
• InChIKey: XOZLHJMDLKDZAL-UHFFFAOYSA-N
• SMILES: CC1=C(SC2=C1N=C(N=C2N3CCOCC3)C4=CN=C(N=C4)N)C5(COC5)OC

GNE-317(CAT: I001511) is a powerful inhibitor targeting the PI3K/mTOR pathway and possesses the capability to traverse the blood-brain barrier. Its unique ability to effectively suppress the PI3K pathway in the brain of mice, even with an intact blood-brain barrier, highlights its potential for therapeutic applications involving neurological conditions. By modulating this pathway, GNE-317 may offer promising prospects for treating disorders that involve dysregulation of the PI3K/mTOR signaling cascade within the central nervous system.

Reference

1:Drug Metab Dispos. 2014 Jul;42(7):1110-6. doi: 10.1124/dmd.114.057513. Epub 2014 Apr 22. 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,Shahidi-Latham S,Quiason C,Barck K,Nishimura M,Alicke B,Pang J,Carano RA,Olivero AG,Phillips HS, PMID: 24754926 DOI: 10.1124/dmd.114.057513
Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing blood-brain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrast-enhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6-fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain-to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.