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

TLDR

The PI3K/Akt/mTOR pathway is frequently constitutively activated in human tumor cells, offering a target for anticancer therapy. NVP‑BEZ235, an imidazo[4,5‑c]quinoline derivative, inhibits PI3K and mTOR by binding their ATP‑binding clefts and shows a dose‑dependent inhibition of the PI3K/Akt pathway in tumor tissues. In vitro, NVP‑BEZ235 induces G1 arrest in human tumor cell lines, and in vivo it is well tolerated, produces disease stasis when given orally, enhances efficacy of other anticancer agents, and is currently in phase I clinical trials. Mol Cancer Ther 2008;7(7):1–13, 1851–13.

Abstract

Abstract 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 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G1 arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 [Mol Cancer Ther 2008;7(7):1851–13]