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

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]

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