Inhibitors of phosphatidylinositol signalling as antiproliferative agents.
Intracellular signalling pathways mediating the effects of oncogenes on cell growth and transformation offer novel targets for the development of anticancer drugs. With this approach it may be sufficient to target a component of the signalling pathway activated by the oncogene rather than the oncogene product itself. Phosphatidylinositol (PtdIns) is a key component of two growth factor signalling pathways. It acts as a substrate for PtdIns specific phospholipase C (PtdInsPLC) and for PtdIns-3-kinase. In this review the antiproliferative properties of some inhibitors of PtdInsPLC and PtdIns-3-kinase are considered. There are some compounds already in clinical trial as anticancer drugs that may act by inhibiting PtdIns signalling, as well as several compounds in preclinical development. Some problems that may be encountered in developing this new class of anticancer drugs are discussed.
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Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson 85724.
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010716:Phosphatidylinositols / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D010716:Phosphatidylinositols; D010726:Phosphodiesterase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010727:Phosphoric Diester Hydrolases; D043265:Phosphatidylinositol Diacylglycerol-Lyase