Cancer can be considered a disease of altered intercellular signalling. The goal of these studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective treatment and prevention of cancer. The signalling targets which will be used include enzymes of phospholipid signaliing (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP- kinase) and enzymes that regulate the cell Cycle (cdc26 phosphatase and cdk4 kinase). The sources of the natural products will be plants used in traditional Chinese medicine, native Americans' medicinal plants, fungal extracts, and combinatorial libraries of natural product derived molecules (""""""""progenomers""""""""). Identified collaborators in China will provide, via Hong Kong, plants which cover the major habitats of herbal growth in China. Readily available natural products with interesting biological activities, will be used as """"""""biological scaffolds"""""""" to prepare diverse mixtures of products (~progenomers"""""""") by use of non-selective reagents, reaction and/or reaction conditions. Active leads will be identified by bioassay-directed fingerprinting using high performance liquid chromatography to obtain for each crude extract or mixture of """"""""progenomers"""""""", fractions in 96 well microtiter plates, which will be submitted for screening. Fingerprints of each of these fractions will be available in the form of ultraviolet/visible spectra collected by a diode array detector and stored in a data bank. On identification of active fractions, the original reference plate will be retrieved and mass spectra and NMR and other spectral data will be collected on the active wells to complete the fingerprinting. This fingerprint will be used to recollect the desired material for further purification and testing Structure elucidation will be done by state of the art methods in organic chemistry. Compounds of analogous structures to those found to be active will be obtained by synthesis or from other sources, where practical, and screened. The pure compounds exhibiting activity in the biochemical target screens will be evaluated for growth inhibitory activity against tumor cells in vitro and those compounds of sufficient in vitro activity will be further evaluated in vivo. Preclinical development of promising lead compounds will be carried out by our commercial collaborator.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19CA052995-07
Application #
5207663
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1996
Total Cost
Indirect Cost
Ihle, N T; Powis, G; Kopetz, S (2011) PI-3-Kinase inhibitors in colorectal cancer. Curr Cancer Drug Targets 11:190-8
Liu, Enbo; Knutzen, Christine A; Krauss, Sybille et al. (2011) Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 108:8680-5
Gwak, Ho-Shin; Shingu, Takashi; Chumbalkar, Vaibhav et al. (2011) Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer 128:787-96
Ihle, Nathan T; Powis, Garth (2010) Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol Aspects Med 31:135-44
Leone, Marilisa; Barile, Elisa; Vazquez, Jesus et al. (2010) NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH. Chem Biol Drug Des 76:10-6
Ihle, Nathan T; Powis, Garth (2010) The biological effects of isoform-specific PI3-kinase inhibition. Curr Opin Drug Discov Devel 13:41-9
Koul, Dimpy; Shen, Ruijun; Kim, Yong-Wan et al. (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559-69
Gaitonde, Supriya; De, Surya K; Tcherpakov, Marianna et al. (2009) BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. Pigment Cell Melanoma Res 22:187-95
Ihle, Nathan T; Lemos, Robert; Schwartz, David et al. (2009) Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther 8:94-100
Ihle, Nathan T; Lemos Jr, Robert; Wipf, Peter et al. (2009) Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143-50

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