Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Molecular Cancer Therapeutics - Tập 11 Số 2 - Trang 317-328 - 2012
Sauveur‐Michel Maira1, Sabina Pecchi1, Alan Huang1, Matthew T. Burger1, Mark Knapp1, Dario Sterker1, Christian Schnell1, Daniel Guthy1, Tobi Nagel1, Marion Wiesmann1, Saskia M. Brachmann1, Christine Fritsch1, Marion Dorsch1, Patrick Chêne1, Kevin Shoemaker1, Alain De Pover1, Daniel L. Menezes1, Georg Martiny‐Baron1, Doriano Fabbro1, Christopher J. Wilson1, Robert Schlegel1, Francesco Hofmann1, Carlos García‐Echeverría1, William R. Sellers1, Charles F. Voliva1
1Authors' Affiliations: 1Oncology Disease Area, 2Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland; 3Oncology Disease Area, Novartis Institutes for Biomedical Research, Emeryville, California; 4Oncology Translational Medicine, BU Oncology, Novartis Pharma Inc.; 5Developmental and Molecular Pathways, and 6Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts

Tóm tắt

Abstract Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Kα mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer. Mol Cancer Ther; 11(2); 317–28. ©2011 AACR.

Từ khóa


Tài liệu tham khảo

Hawkins, 2006, Signalling through Class I PI3Ks in mammalian cells, Biochem Soc Trans, 34, 647, 10.1042/BST0340647

Zhao, 2008, Class I PI3K in oncogenic cellular transformation, Oncogene, 27, 5486, 10.1038/onc.2008.244

Yuan, 2008, PI3K pathway alterations in cancer: variations on a theme, Oncogene, 27, 5497, 10.1038/onc.2008.245

Lee-Hoeflich, 2008, A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy, Cancer Res, 68, 5878, 10.1158/0008-5472.CAN-08-0380

Samuels, 2004, High frequency of mutations of the PIK3CA gene in human cancers, Science, 304, 554, 10.1126/science.1096502

Carpten, 2007, A transforming mutation in the pleckstrin homology domain of AKT1 in cancer, Nature, 448, 439, 10.1038/nature05933

Markman, 2010, Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs, Oncotarget, 1, 530, 10.18632/oncotarget.188

Maira, 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, Mol Cancer Ther, 7, 1851, 10.1158/1535-7163.MCT-08-0017

Fayard, 2010, Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway, Curr Top Microbiol Immunol, 346, 31

Carracedo, 2006, The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells, Cancer Cell, 9, 301, 10.1016/j.ccr.2006.03.005

Courtney, 2010, The PI3K pathway as drug target in human cancer, J Clin Oncol, 28, 1075, 10.1200/JCO.2009.25.3641

van der Heijden, 2010, Inhibition of the PI3K pathway: hope we can believe in?, Clin Cancer Res, 16, 3094, 10.1158/1078-0432.CCR-09-3004

Garcia-Echeverria, 2004, In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase, Cancer Cell, 5, 231, 10.1016/S1535-6108(04)00051-0

Fuchikami, 2002, 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, 7, 441, 10.1177/108705702237676

Palmer, 1991, Undersanding enzymes, 3rd ed

Morgenstern, 1990, Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line, Nucleic Acids Res, 18, 3587, 10.1093/nar/18.12.3587

Zhao, 2005, The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells, Proc Natl Acad Sci U S A, 102, 18443, 10.1073/pnas.0508988102

Zhang, 2003, Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR, J Clin Invest, 112, 1223, 10.1172/JCI200317222

Brachmann, 2009, 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, 106, 22299, 10.1073/pnas.0905152106

van, 2009, Tracing pathway activities with kinase inhibitors and reverse phase protein arrays, Proteomics Clin Appl, 3, 412, 10.1002/prca.200800070

Clarke, 1997, 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, 46, 255, 10.1023/A:1005938428456

Schnell, 2008, Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging, Cancer Res, 68, 6598, 10.1158/0008-5472.CAN-08-1044

Sutherlin, 2010, 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, 53, 1086, 10.1021/jm901284w

Walker, 1999, Structural insights into phosphoinositide 3-kinase catalysis and signalling, Nature, 402, 313, 10.1038/46319

Walker, 2000, Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine, Mol Cell, 6, 909, 10.1016/S1097-2765(05)00089-4

Liu, 2009, Targeting the phosphoinositide 3-kinase pathway in cancer, Nat Rev Drug Discov, 8, 627, 10.1038/nrd2926

Chresta, 2010, 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, 70, 288, 10.1158/0008-5472.CAN-09-1751

Engelman, 2009, Targeting PI3K signalling in cancer: opportunities, challenges and limitations, Nat Rev Cancer, 9, 550, 10.1038/nrc2664

Yaguchi, 2006, Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor, J Natl Cancer Inst, 98, 545, 10.1093/jnci/djj133

Engelman, 2008, Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers, Nat Med, 14, 1351, 10.1038/nm.1890

Chandarlapaty, 2011, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity, Cancer Cell, 19, 58, 10.1016/j.ccr.2010.10.031

Serra, 2011, PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer, Oncogene, 30, 2547, 10.1038/onc.2010.626

Chakrabarty, 2011 28, 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

Garrett, 2011, Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase, Proc Natl Acad Sci U S A, 108, 5021, 10.1073/pnas.1016140108

Graupera, 2008, Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration, Nature, 453, 662, 10.1038/nature06892

Yuan, 2008, Class 1A PI3K regulates vessel integrity during development and tumorigenesis, Proc Natl Acad Sci U S A, 105, 9739, 10.1073/pnas.0804123105

Burger, 2011, Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 Kinase inhibitor for treating cancer, ACS Med Chem Lett, 2, 774, 10.1021/ml200156t

O'Brien, 2010, Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models, Clin Cancer Res, 16, 3670, 10.1158/1078-0432.CCR-09-2828

Dan, 2010, Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations, Cancer Res, 70, 4982, 10.1158/0008-5472.CAN-09-4172

Wee, 2008, PTEN-deficient cancers depend on PIK3CB, Proceedings of the National Academy of Sciences, 13057

Jia, 2008, Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis, Nature, 454, 776, 10.1038/nature07091

Halilovic, 2010, PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling, Cancer Res, 70, 6804, 10.1158/0008-5472.CAN-10-0409

Kong, 2009, Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, Eur J Cancer, 45, 857, 10.1016/j.ejca.2008.12.007

Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 11 Số 2

317-328

Thông tin tác giả