The intermediate enzymes of isoprenoid metabolism as anticancer targets

Andrew J Wiemer; Raymond J Hohl; David F Wiemer

doi:10.2174/187152009788451860

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The intermediate enzymes of isoprenoid metabolism as anticancer targets

Journal article

Peer reviewed

The intermediate enzymes of isoprenoid metabolism as anticancer targets

Andrew J Wiemer, Raymond J Hohl and David F Wiemer

Anti-cancer agents in medicinal chemistry, Vol.9(5), pp.526-542

06/2009

DOI: 10.2174/187152009788451860

PMID: 19519294

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Abstract

Inhibitors of isoprenoid biosynthesis are widely used to treat human disease including statins and nitrogenous bisphosphonates. Due to the importance of core human isoprenoid biosynthesis for diverse cellular processes related to cancer cell growth and metastasis, inhibition of this pathway may produce beneficial anticancer consequences. For example, ras oncogenes are well known; ras proteins are overexpressed in many human cancers, and these proteins must be isoprenylated to function. The rho proteins are important for regulating cell motility, and also must be isoprenylated. This has drawn significant attention to inhibitors of protein prenyl transferases. In addition to the reactions that are targeted in current clinical applications, there are other enzymes that have not been studied as extensively. Inhibition of these enzymes, from mevalonate kinase to geranylgeranyl diphosphate synthase, could be attractive as a single agent therapy or in combination with current agents for treatment of cancers in which isoprenylated proteins have been implicated. While detailed in vivo data for many of these putative targets is lacking, there have been several breakthroughs in recent years that could facilitate further studies. In particular, compounds that specifically inhibit some of the downstream isoprenoid biosynthesis enzymes have been developed and their effects in cancer models are emerging. This review will discuss current knowledge of these lesser known isoprenoid pathway enzymes, identify trends in the development of their small molecule inhibitors, and describe the applications and effects of these compounds in cancer models.

Animals

Antimetabolites, Antineoplastic - chemistry

Antimetabolites, Antineoplastic - pharmacology

Antimetabolites, Antineoplastic - therapeutic use

Diphosphonates - chemistry

Diphosphonates - pharmacology

Diphosphonates - therapeutic use

Enzyme Inhibitors - chemistry

Enzyme Inhibitors - pharmacology

Enzyme Inhibitors - therapeutic use

Farnesyltranstransferase - antagonists & inhibitors

Farnesyltranstransferase - metabolism

Humans

Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry

Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology

Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use

Neoplasms - drug therapy

Prenylation - drug effects

Terpenes - antagonists & inhibitors

Terpenes - metabolism

Details

Title: Subtitle: The intermediate enzymes of isoprenoid metabolism as anticancer targets
Creators: Andrew J Wiemer
Raymond J Hohl
David F Wiemer
Resource Type: Journal article
Publication Details: Anti-cancer agents in medicinal chemistry, Vol.9(5), pp.526-542
DOI: 10.2174/187152009788451860
PMID: 19519294
ISSN: 1871-5206
eISSN: 1875-5992
Language: English
Date published: 06/2009
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9984216689002771

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