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Non-peptidic prenyltransferase inhibitors: diverse structural classes and surprising anti-cancer mechanisms
R A Gibbs1, T J Zahn, J S Sebolt-Leopold
1Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, 528 Shapero Hall, Detroit, MI 48202, USA. rag@wizard.pharm.wayne.edu
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.
Insights
Farnesyltransferase inhibitors (FTIs) are a promising anticancer drug class targeting Ras oncoproteins. This review critically appraises FTI development, anticancer activity, and clinical trial progress.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Protein prenylation is crucial for Ras oncoprotein function.
- Farnesyltransferase (FTase) is a key enzyme in this process and a target for anticancer drugs.
- Farnesyltransferase inhibitors (FTIs) have emerged as a significant area in anticancer drug development.
Purpose of the Study:
- To provide a comprehensive overview of farnesyltransferase inhibitor (FTI) development.
- To critically evaluate the anticancer activity and potential of various FTI classes.
- To discuss the discovery, mechanism of action, and clinical progress of FTIs.
Main Methods:
- Review of historical developments in protein prenylation and FTase enzyme discovery.
- Categorization of FTIs into natural products, CAAX-competitive inhibitors, and FPP-competitive inhibitors.
- Analysis of FTI efficacy in preclinical cancer models and discussion of clinical trial data.
Main Results:
- Numerous potent FTIs have been developed across diverse structural classes.
- FPP-competitive inhibitors show particular promise with novel structural motifs.
- FTIs exhibit distinct mechanisms from traditional cytotoxic agents, with some showing surprising efficacy.
Conclusions:
- FTIs represent a significant advancement in targeted cancer therapy.
- Ongoing clinical trials are vital for understanding the full therapeutic potential and mechanistic nuances of FTIs.
- Further research into novel FTI structures and their precise antitumor properties is warranted.