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Non-peptidic prenyltransferase inhibitors: diverse structural classes and surprising anti-cancer mechanisms.

Abstract
The development of farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras oncoprotein in driving the discovery of prenyltransferase enzymes. The different classes of prenylated proteins will be described along with the biochemical characteristics of the key drug target--farnesyltransferase (FTase). Numerous potent farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of action: a) natural products; b) peptidomimetics and other CAAX-competitive inhibitors; c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.
AuthorsR A Gibbs, T J Zahn, J S Sebolt-Leopold
JournalCurrent medicinal chemistry (Curr Med Chem) Vol. 8 Issue 12 Pg. 1437-65 (Oct 2001) ISSN: 0929-8673 [Print] United Arab Emirates
PMID11562276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)
Chemical References
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Dimethylallyltranstransferase
Topics
  • Antineoplastic Agents (pharmacology)
  • Clinical Trials as Topic
  • Dimethylallyltranstransferase (antagonists & inhibitors)
  • Enzyme Inhibitors (pharmacology)
  • Humans
  • Neoplasms (drug therapy, metabolism, pathology)

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