Phosphatidylinositol-3-kinase (PtdIns-3-kinase) is an important constituent Of growth factor and oncogene signaling pathways and is an attractive target for anticancer drug development. The metabolic products of PtdIns-3-kinase, PtdIns-3-mono and -poly phosphates bind to specific protein domains including the pleckstrin homology (PH) domain, to regulate protein-protein interactions and enzyme activities that are critical to cancer cell growth. We have developed a novel approach to inhibiting PtdIns-3-kinase signaling based on the use of D-3-deoxy-myo- inositol-PtdIns that cannot be metabolized by PtIns-3-kinase and that act as downstream inhibitors of the effects of PtdIns-3- phosphates. We have identified lead D-3-deoxy-PtdIns that inhibit PH domain activation by PtdIns-3-kinase and that have in vivo antitumor activity. We have also synthesized a novel class of 3-deoxy-myo-inositol sphingosine lipids that may act like ceramide, a complex sphingosine lipid that is a key signaling molecule in inducing cancer cell apoptosis. We will develop further both classes of compounds as potential antitumor agents. We will explore modifications of the inositol ring including an examination of carbohydrate surrogates, modification of the glycerol moiety including a study of sphingosine-inositol conjugates, and replacements for the phosphate group. We will use the compounds in mechanistic studies to delineate the role of PtdIns-3-phosphate signaling and inositol-sphingosines in cancer cell growth and death, and we will study the most active compounds as potential antitumor agents.
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