Biological Activity
gne-477 is a potent dual pi3k/mtor inhibitor. owing to the common association with oncogenic malignancies, 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-α, β, δ, and γ with ic50s of 4, 86, 6, and 15 nm, respectively. [1].
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 [1].
References
[1] heffron tp,berry m,castanedo g,chang c,chuckowree i,dotson j,folkes a,gunzner j,lesnick jd,lewis c,mathieu s,nonomiya j,olivero a,pang j,peterson d,salphati l,sampath d,sideris s,sutherlin dp,tsui v,wan nc,wang s,wong s,zhu by. identification of gne-477, a potent and efficacious dual pi3k/mtor inhibitor. bioorg med chem lett.2010 apr 15;20(8):2408-11.
