PROBES FOR ENZYMES OF THE PHOSPHOINOSITIDE PATHWAY

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This proposal is a plan to design, synthesize and evaluate a number of inositol and phosphatidylinositol (PI) analogues as selective probes for key enzymes in the phosphoinositide pathway. The biological goal is to gain understanding, through the use of biochemical probes, into the regulation of cell growth, and, hopefully, cancer. The strategy is essentially threefold: (1) Design, synthesis, and evaluation of suitable fraudulent cyclitols that are substrates and/or inhibitors for phosphatidylinositol synthetase (PI synthetase). (2) Study, either through synthetic or biosynthetically produced fraudulent analogues, their effects on the other enzymes: phosphatidyl inositol kinase (PI kinase), phosphatidylinositol-4-phosphate kinase (PIP kinase) and phospholipase C. This component of the project allows for strategically modified PI's to be evaluated as rationally designed inhibitors. (3) Finally, a series of phosphonate analogues to be designed on the basis of the results of these enzyme studies are proposed as possible membrane-permeable PI analogues. Our primary interest in designing probes for these enzymes, which are believed to be key factors in the intracellular communication process, stems from the possibility that neoplastic growth may result, at least in part, from an altered response to growth factors, of which the enzymes of the PI pathway play a fundamental role. The discovery of hormone and growth factor induced PIP hydrolysis by phospholipase C suggests that these enzymes are viable new targets for drug design. As some specificity could result because cells differ in specific growth factors to which they respond, one might predict that it should be possible to target a narrower subset of proliferative cells than is possible with the usual chemotherapeutic agents which block ubiquitous and essential cellular processes.