? Phosphoinositides are key lipid second messengers in many cellular signaling processes. In particular, the activity of phosphatidylinositol 3-kinase (PI 3-K), and the synthesis of its lipid products, is important in pathways mediating cell proliferation, survival, and motility. Alterations in PI 3-K mediated signaling are common to many cancers. Targeting PI 3-K activity is recognized as a potential anti-cancer strategy. The lipid products of PI 3-K act as second messengers by activating downstream protein effectors by their recruitment to specific domains in the plasma membrane. We propose a new strategy for inhibiting PI 3-K mediated signaling in disease by preventing the interaction of PI(3,4,5)P3 with these protein effectors. In vitro and cell-based assays will be developed to determine the interaction of selected effectors with PI(3,4,5)P3. These will be used to identify compounds which block the interaction of PI(3,4,5)P3 with effector proteins using libraries of synthetic small molecules and of compounds from natural sources. The mode of action of inhibitors will also be explored in cell culture. Identification and characterization of novel antagonists of PI 3-K signaling may lead to new therapies for cancer, inflammation, and diabetes. ? ?
