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. – ScienceOpen
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      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.

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          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 G(1) 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.

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          Author and article information

          Journal
          Mol Cancer Ther
          Molecular cancer therapeutics
          American Association for Cancer Research (AACR)
          1535-7163
          1535-7163
          Jul 2008
          : 7
          : 7
          Affiliations
          [1 ] Oncology Disease Area, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH4002 Basel, Switzerland. sauveur-michel.maira@novartis.com
          Article
          1535-7163.MCT-08-0017
          10.1158/1535-7163.MCT-08-0017
          18606717
          c0ed7421-e7e6-4baa-a2a0-6a70b5640d4b
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