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Cancer Research 67, 5840-5850, June 15, 2007. doi: 10.1158/0008-5472.CAN-06-4615
© 2007 American Association for Cancer Research

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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases

Florence I. Raynaud1, Suzanne Eccles1, Paul A. Clarke1, Angela Hayes1, Bernard Nutley1, Sonia Alix1, Alan Henley1, Francesca Di-Stefano1, Zahida Ahmad1, Sandrine Guillard1, Lynn M. Bjerke1, Lloyd Kelland1, Melanie Valenti1, Lisa Patterson1, Sharon Gowan1, Alexis de Haven Brandon1, Masahiko Hayakawa2, Hiroyuki Kaizawa2, Tomonubu Koizumi2, Takahide Ohishi2, Sonal Patel3, Nahid Saghir3, Peter Parker4, Mike Waterfield5 and Paul Workman1

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{alpha} (2 nmol/L), p110ß (3 nmol/L), p110{delta} (3 nmol/L), and p110{gamma} (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]




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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]




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2007 by the American Association for Cancer Research.