GNE-477

Description: GNE-477 is a novel, potent and efficacious dual inhibitor of PI3K (IC50=4 nM)/mTOR(Ki=21 nM). The PI3K/AKT/mTOR signaling pathway is regarded as an attractive area of research for the identification of oral small molecule inhibitors. In vitro, GNE-477 was found to inhibit PI3K-alpha, beta, delta, and gamma with IC50s of 4, 86, 6, and 15 nM, respectively. In vivo, a direct comparison of GNE-477 with its des-methyl analog revealed that the trend of reduced in vivo clearance in rats is also observed in dogs and mice. The clearance improvement was significant in dogs where the des-methyl analog was cleared at two-thirds the rate of hepatic blood flow while GNE-477 had low clearance. In an study evaluating the tumor growth inhibition of a PC3 tumor xenograft10 over 14 days, stasis was achieved at a 20 mg/kg QD dose of GNE-477 and significant inhibition was found with doses as low as 1 mg/kg QD. GNE-477 was generally well tolerated during this study as shown by acceptable levels of weight loss comparable to that in the vehicle cohort

References: Bioorg Med Chem Lett. 2010 Apr 15; 20(8):2408-11.