Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

摘要: The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft these enzymes. In cellular settings using cell lines, this molecule able effectively specifically block dysfunctional activation pathway, inducing G(1) arrest. translates well vivo models cancer. Thus, compound was tolerated, displayed disease stasis when administered orally, enhanced efficacy other agents used combination studies. Ex pharmacokinetic/pharmacodynamic analyses tissues showed a time-dependent correlation between concentration PI3K/Akt inhibition. Collectively, preclinical data show potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. currently phase I clinical trials.