| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow and McElwain Laboratories, Sutton, Surrey, United Kingdom; 2 Astellas Pharma, Inc., Drug Discovery Research, Tsukuba, Ibaraki, Japan; 3 PIramed Ltd., Slough, Berkshire, United Kingdom; 4 Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories; and 5 Ludwig Institute for Cancer Research, Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
Requests for reprints: Florence I. Raynaud, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey, United Kingdom, SM2 5NG. Phone: 44-2087224212; E-mail: Florence.Raynaud{at}icr.ac.uk and Paul Workman, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey, United Kingdom. E-mail: Paul.Workman{at}icr.ac.uk.
Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110
(2 nmol/L), p110ß (3 nmol/L), p110
(3 nmol/L), and p110
(15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 µmol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic. [Cancer Res 2007;67(12):5840–50]
This article has been cited by other articles:
|
|
 |
|
  W. Link, J. Oyarzabal, B. G. Serelde, M. I. Albarran, O. Rabal, A. Cebria, P. Alfonso, J. Fominaya, O. Renner, S. Peregrina, et al. Chemical Interrogation of FOXO3a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases J. Biol. Chem., October 9, 2009; 284(41): 28392 - 28400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Bax, N. Gaspar, S. E. Little, L. Marshall, L. Perryman, M. Regairaz, M. Viana-Pereira, R. Vuononvirta, S. Y. Sharp, J. S. Reis-Filho, et al. EGFRvIII Deletion Mutations in Pediatric High-Grade Glioma and Response to Targeted Therapy in Pediatric Glioma Cell Lines Clin. Cancer Res., September 15, 2009; 15(18): 5753 - 5761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Markman, F. Atzori, J. Perez-Garcia, J. Tabernero, and J. Baselga Status of PI3K inhibition and biomarker development in cancer therapeutics Ann. Onc., August 27, 2009; (2009) mdp347v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Qayum, R. J. Muschel, J. H. Im, L. Balathasan, C. J. Koch, S. Patel, W. G. McKenna, and E. J. Bernhard Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling Cancer Res., August 1, 2009; 69(15): 6347 - 6354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sarker, A. H.M. Reid, T. A. Yap, and J. S. de Bono Targeting the PI3K/AKT Pathway for the Treatment of Prostate Cancer Clin. Cancer Res., August 1, 2009; 15(15): 4799 - 4805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hersey, L. Bastholt, V. Chiarion-Sileni, G. Cinat, R. Dummer, A. M. M. Eggermont, E. Espinosa, A. Hauschild, I. Quirt, C. Robert, et al. Small molecules and targeted therapies in distant metastatic disease Ann. Onc., August 1, 2009; 20(suppl_6): vi35 - vi40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. I. Raynaud, S. A. Eccles, S. Patel, S. Alix, G. Box, I. Chuckowree, A. Folkes, S. Gowan, A. De Haven Brandon, F. Di Stefano, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941 Mol. Cancer Ther., July 1, 2009; 8(7): 1725 - 1738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Martin-Fernandez, J. Bales, C. Hodgkinson, A. Welman, M. J. Welham, C. Dive, and C. J. Morrow Blocking Phosphoinositide 3-Kinase Activity in Colorectal Cancer Cells Reduces Proliferation but Does Not Increase Apoptosis Alone or in Combination with Cytotoxic Drugs Mol. Cancer Res., June 1, 2009; 7(6): 955 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Henzi, W.-V. Blum, M. Pfefferli, T. J. Kawecki, V. Salicio, and B. Schwaller SV40-Induced Expression of Calretinin Protects Mesothelial Cells from Asbestos Cytotoxicity and May Be a Key Factor Contributing to Mesothelioma Pathogenesis Am. J. Pathol., June 1, 2009; 174(6): 2324 - 2336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Niedermeier, B. T. Hennessy, Z. A. Knight, M. Henneberg, J. Hu, A. V. Kurtova, W. G. Wierda, M. J. Keating, K. M. Shokat, and J. A. Burger Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach Blood, May 28, 2009; 113(22): 5549 - 5557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. Zou, K. D. Smith, Q.-S. Zhu, J. Liu, I. E. McCutcheon, J. M. Slopis, F. Meric-Bernstam, Z. Peng, W. G. Bornmann, G. B. Mills, et al. Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor Mol. Cancer Ther., May 1, 2009; 8(5): 1157 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Chiarini, F. Fala, P. L. Tazzari, F. Ricci, A. Astolfi, A. Pession, P. Pagliaro, J. A. McCubrey, and A. M. Martelli Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia Cancer Res., April 15, 2009; 69(8): 3520 - 3528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marone, D. Erhart, A. C. Mertz, T. Bohnacker, C. Schnell, V. Cmiljanovic, F. Stauffer, C. Garcia-Echeverria, B. Giese, S.-M. Maira, et al. Targeting Melanoma with Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors Mol. Cancer Res., April 1, 2009; 7(4): 601 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. S. Boyd, Q. J. Wu, C. O'Brien, J. Spoerke, H. Savage, P. J. Fielder, L. Amler, Y. Yan, and M. R. Lackner Proteomic analysis of breast cancer molecular subtypes and biomarkers of response to targeted kinase inhibitors using reverse-phase protein microarrays Mol. Cancer Ther., December 1, 2008; 7(12): 3695 - 3706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wee, D. Wiederschain, S.-M. Maira, A. Loo, C. Miller, R. deBeaumont, F. Stegmeier, Y.-M. Yao, and C. Lengauer PTEN-deficient cancers depend on PIK3CB PNAS, September 2, 2008; 105(35): 13057 - 13062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Biswas, Y. Zhao, A. Nagalingam, T. W. Gardner, and L. Sandirasegarane PDGF- and Insulin/IGF-1-Specific Distinct Modes of Class IA PI 3-Kinase Activation in Normal Rat Retinas and RGC-5 Retinal Ganglion Cells Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3687 - 3698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Prevo, E. Deutsch, O. Sampson, J. Diplexcito, K. Cengel, J. Harper, P. O'Neill, W. G. McKenna, S. Patel, and E. J. Bernhard Class I PI3 Kinase Inhibition by the Pyridinylfuranopyrimidine Inhibitor PI-103 Enhances Tumor Radiosensitivity Cancer Res., July 15, 2008; 68(14): 5915 - 5923. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
