title: 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.
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.
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH4002 Basel, Switzerland. sauveur-michel.maira@novartis.com
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Frédéric
authors.initials: F
authors.lastname: Stauffer
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.forename: Saskia
authors.initials: S
authors.lastname: Brachmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Kevin
authors.initials: K
authors.lastname: Schoemaker
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Daniela
authors.initials: D
authors.lastname: Gabriel
authors.forename: Marjo
authors.initials: M
authors.lastname: Simonen
authors.forename: Leon
authors.initials: L
authors.lastname: Murphy
authors.forename: Peter
authors.initials: P
authors.lastname: Finan
authors.forename: William
authors.initials: W
authors.lastname: Sellers
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib