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

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]

[1]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[2]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[3]  J. Woodgett.  Recent advances in the protein kinase B signaling pathway. , 2005, Current opinion in cell biology.

[4]  G. Mills,et al.  Inhibition of the phosphatidylinositol 3'-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. , 2002, Molecular cancer therapeutics.

[5]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[7]  P. Furet,et al.  Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. , 2008, Bioorganic & medicinal chemistry letters.

[8]  A. Prescott,et al.  The in vivo role of PtdIns(3,4,5)P3 binding to PDK1 PH domain defined by knockin mutation , 2004, The EMBO journal.

[9]  M. Loda,et al.  The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells , 2005 .

[10]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[11]  P. Vogt,et al.  Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Christian Ried,et al.  Structural insights into phosphoinositide 3-kinase catalysis and signalling , 1999, Nature.

[13]  K. Shokat,et al.  Chemically targeting the PI3K family. , 2007, Biochemical Society transactions.

[14]  D. Guertin,et al.  Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. , 2006, Developmental cell.

[15]  G. Prendergast.  Molecular cancer therapeutics : strategies for drug discovery and development , 2005 .

[16]  G. Mills,et al.  Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. , 2002, Cancer research.

[17]  P. Vogt,et al.  Cancer-specific mutations in PIK3CA are oncogenic in vivo , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Woo,et al.  Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. , 2006, Developmental cell.

[19]  David J. Kwiatkowski,et al.  Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Hirono,et al.  Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. , 2006, Journal of the National Cancer Institute.

[22]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[23]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[24]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[25]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[26]  Michael Q. Zhang,et al.  From worm to human: bioinformatics approaches to identify FOXO target genes , 2005, Mechanisms of Ageing and Development.

[27]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[28]  K. Kinzler,et al.  The Structure of a Human p110a/p85a Complex Elucidates the Effects of Oncogenic PI3Ka Mutations , 2007 .

[29]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[30]  K. Inoki,et al.  Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. , 2006, Genes & development.

[31]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[32]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[33]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[34]  T. Okabe,et al.  High-throughput screening with quantitation of ATP consumption: a universal non-radioisotope, homogeneous assay for protein kinase. , 2004, Assay and drug development technologies.

[35]  Jacob D. Jaffe,et al.  mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s , 2006, Current Biology.

[36]  C. García-echeverría,et al.  Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery. , 2008, Expert opinion on therapeutic targets.

[37]  J. Qin,et al.  SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity , 2006, Cell.

[38]  Bert Vogelstein,et al.  The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations , 2007, Science.

[39]  W. Mason,et al.  Drug Insight: temozolomide as a treatment for malignant glioma—impact of a recent trial , 2005, Nature Clinical Practice Neurology.

[40]  S. Lees-Miller,et al.  DNA damage-induced activation of ATM and ATM-dependent signaling pathways. , 2004, DNA repair.

[41]  J. Blenis,et al.  Inactivation of the Tuberous Sclerosis Complex-1 and -2 Gene Products Occurs by Phosphoinositide 3-Kinase/Akt-dependent and -independent Phosphorylation of Tuberin* , 2003, Journal of Biological Chemistry.

[42]  N. Hay,et al.  Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. , 2006, Cancer cell.

[43]  M. Tsao,et al.  Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  J. Dodge,et al.  Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. , 1994, Cancer research.

[45]  Roger L. Williams,et al.  Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. , 2000, Molecular cell.

[46]  D. Fabbro,et al.  In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. , 2004, Cancer cell.

[47]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[48]  R. Medema,et al.  Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty , 2003, Journal of leukocyte biology.

[49]  M. Berger,et al.  Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. , 2005, Cancer research.

[50]  R. Stein.  Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. , 2001, Endocrine-related cancer.

[51]  P. Hawkins,et al.  Signalling through Class I PI3Ks in mammalian cells. , 2006, Biochemical Society transactions.