Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor

Molecular Cancer Therapeutics

Volumn 11, Issue 2, 2012, Pages 317-328

  Maira, Sauveur Michel ^a   Pecchi, Sabina ^b   Huang, Alan ^a   Burger, Matthew ^b   Knapp, Mark ^b   Sterker, Dario ^a   Schnell, Christian ^a   Guthy, Daniel ^a   Nagel, Tobi ^b   Wiesmann, Marion ^a   Brachmann, Saskia ^a   Fritsch, Christine ^a   Dorsch, Marion ^a,e   Chène, Patrick ^a   Shoemaker, Kevin ^b   De Pover, Alain ^a   Menezes, Daniel ^b   Martiny Baron, Georg ^a   Fabbro, Doriano ^a   Wilson, Christopher J ^c   Schlegel, Robert ^a   Hofmann, Francesco ^a   García Echeverría, Carlos ^a,d   Sellers, William R ^b   Voliva, Charles F ^b   more..

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^c Developmental and Molecular Pathways   (United States)

^d SANOFI   (France)

^e Sanofi Aventis   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; DOCETAXEL; MAMMALIAN TARGET OF RAPAMYCIN; NVP BKM 120; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE; PROTEIN KINASE B; SELUMETINIB; TEMOZOLOMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG IDENTIFICATION; DRUG SAFETY; GENE MUTATION; IN VIVO STUDY; MOUSE; NONHUMAN; ONCOGENE K RAS; PRIORITY JOURNAL; TUMOR CELL; TUMOR CELL LINE; XENOGRAFT;

ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; BIOLOGICAL AVAILABILITY; BLOTTING, WESTERN; CELL LINE, TUMOR; DOSE-RESPONSE RELATIONSHIP, DRUG; HCT116 CELLS; HT29 CELLS; HUMANS; ISOENZYMES; MICE; MICE, NUDE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MORPHOLINES; MUTATION; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-AKT; RATS; TUMOR BURDEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84856826293     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-11-0474     Document Type: Article

References (43)

1. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 2006;34:647-62.
2. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008;27:5486-96.
3. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008;27:5497-510.
4. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008;68: 5878-87.
5. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
6. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-44.
7. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/ mTOR pathway-beyond rapalogs. Oncotarget 2010;1:530-43.
8. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. 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. Mol Cancer Ther 2008;7:1851-63.
9. Fayard E, Xue G, Parcellier A, Bozulic L, Hemmings BA. Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr Top Microbiol Immunol 2010;346:31-56.
10. Carracedo A, Lorente M, Egia A, Blazquez C, Garcia S, Giroux V, et al. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 2006;9:301-12.
11. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
12. van der Heijden MS, Bernards R. Inhibition of the PI3K pathway: hope we can believe in? Clin Cancer Res 2010;16:3094-9.
13. Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, et al. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004;5:231-9.
14. Fuchikami K, Togame H, Sagara A, Satoh T, Gantner F, Bacon KB, et al. A versatile high-throughput screen for inhibitors of lipid kinase activity: development of an immobilized phospholipid plate assay for phosphoinositide 3-kinase gamma. J Biomol Screen 2002;7: 441-50.
15. Palmer T. Undersanding enzymes. 3rd ed. Chichester, England: Ellis Horwood Limited; 1991.
16. Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 1990;18:3587-96.
17. Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3- kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A 2005;102:18443-8.
18. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 2003;112: 1223-33.
19. Brachmann S, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, et al., Specific apoptosis induction by the dual PI3K/mTOR inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A 2009;106:22299-307.
20. van OJ, Calonder C, Rechsteiner D, Ehrat M, Mestan J, Fabbro D, et al. Tracing pathway activities with kinase inhibitors and reverse phase protein arrays. Proteomics Clin Appl 2009;3:412-22.
21. Clarke R. Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res Treat 1997;46:255-78.
22. Schnell CR, Stauffer F, Allegrini PR, O'Reilly T, McSheehy PM, Dartois C, et al. Effects of the dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008;68: 6598-607.
23. Sutherlin DP, Sampath D, Berry M, Castanedo G, Chang Z, Chuckowree I, et al. Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan- PI3-kinase/mTOR inhibitors for the treatment of cancer. J Med Chem 2010;53:1086-97.
24. Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 1999;402:313-20.
25. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000;6:909-19.
26. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627-44.
27. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010;70: 288-98.
28. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62.
29. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006;98:545-56.
30. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14: 1351-6.
31. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic- Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19:58-71.
32. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57.
33. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Breast Cancer Special Feature: Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2011 Feb 28. [Epub ahead of print].
34. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, et al. Transcriptional and posttranslational up- regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A 2011;108:5021-6.
35. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 2008;453: 662-6.
36. Yuan TL, Choi HS, Matsui A, Benes C, Lifshits E, Luo J, et al. Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc Natl Acad Sci U S A 2008;105:9739-44.
37. Burger MT, Pecchi S, Wagman A, Ni Z-J, Knapp M, Hendrickson T, et al. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 Kinase inhibitor for treating cancer. ACS Med Chem Lett 2011;2:774-9.
38. O'Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res 2010;16:3670-83.
39. Dan S, Okamura M, Seki M, Yamazaki K, Sugita H, Okui M, et al. Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. Cancer Res 2010;70:4982-94.
40. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, et al. PTEN-deficient cancers depend on PIK3CB. Proceedings of the National Academy of Sciences 2008;105:13057-62.
41. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, et al. Essential roles of PI (3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 2008;454:776-9.
42. Halilovic E, She QB, Ye Q, Pagliarini R, Sellers WR, Solit DB, et al. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res 2010;70: 6804-14.
43. Kong D, Okamura M, Yoshimi H, Yamori T. Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor. Eur J Cancer 2009;45:857-65.