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

Molecular Cancer Therapeutics - Tập 7 Số 7 - Trang 1851-1863 - 2008
Sauveur‐Michel Maira1, Frédéric Stauffer1, Josef Brueggen1, Pascal Furet1, Christian Schnell1, Christine Fritsch1, Saskia M. Brachmann1, Patrick Chêne1, Alain De Pover1, Kevin Schoemaker2, Doriano Fabbro3, Daniela Gabriel3, Marjo Simonen3, Leon O. Murphy4, Peter M. Finan4, William R. Sellers5, Carlos García-Echeverría1
11Oncology Disease Area and
23Novartis Vaccines and Diagnostics, Inc., Emeryville, California; and
32Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland;
44Developmental and Molecular Pathways and
55Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts

Tóm tắt

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]

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Molecular Cancer Therapeutics

Tập 7 Số 7

1851-1863

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