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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.

Maira, Sauveur-Michel and Stauffer, Frederic and Brueggen, Josef and Furet, Pascal and Schnell, Christian and Fritsch, Christine and Brachmann, Saskia and Chene, Patrick and De Pover, Alain and Schoemaker, Kevin and Fabbro, Doriano and Gabriel, Daniela and Simonen, Marjo and Murphy, Leon and Finan, Peter and Sellers, William and Garcia-Echeverria, Carlos (2008) 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. Molecular Cancer Therapeutics, 7 (7). pp. 1851-1863. ISSN 1535-7163

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
Keywords: PI3K; mTOR; cancer; small-molecule kinase inhibitor
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Date Deposited: 14 Dec 2009 13:56
Last Modified: 31 Jan 2013 01:09
URI: https://oak.novartis.com/id/eprint/684

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