Supplementary Material from 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

Maira, Sauveur-Michel; Stauffer, Frédéric; Brueggen, Josef; Furet, Pascal; Schnell, Christian; Fritsch, Christine; Brachmann, Saskia; Chène, Patrick; De Pover, Alain; Schoemaker, Kevin; Fabbro, Doriano; Gabriel, Daniela; Simonen, Marjo; Murphy, Leon; Finan, Peter; Sellers, William; García-Echeverría, Carlos

doi:10.1158/1535-7163.22484142.v1

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Supplementary Material from 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

journal contribution

posted on 2023-03-31, 23:15 authored by Sauveur-Michel Maira, Frédéric Stauffer, Josef Brueggen, Pascal Furet, Christian Schnell, Christine Fritsch, Saskia Brachmann, Patrick Chène, Alain De Pover, Kevin Schoemaker, Doriano Fabbro, Daniela Gabriel, Marjo Simonen, Leon Murphy, Peter Finan, William Sellers, Carlos García-Echeverría

Supplementary Material from 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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ARTICLE 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]