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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 526-542 |
| Number of pages | 17 |
| Journal | Anti-Cancer Agents in Medicinal Chemistry |
| Volume | 9 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 1 2009 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Pharmacology
- Cancer Research
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The intermediate enzymes of isoprenoid metabolism as anticancer targets. / Wiemer, Andrew J.; Hohl, Raymond J.; Wiemer, David F.
In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 9, No. 5, 01.01.2009, p. 526-542.Research output: Contribution to journal › Review article
TY - JOUR
T1 - The intermediate enzymes of isoprenoid metabolism as anticancer targets
AU - Wiemer, Andrew J.
AU - Hohl, Raymond J.
AU - Wiemer, David F.
PY - 2009/1/1
Y1 - 2009/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=67651096109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651096109&partnerID=8YFLogxK
U2 - 10.2174/187152009788451860
DO - 10.2174/187152009788451860
M3 - Review article
C2 - 19519294
AN - SCOPUS:67651096109
VL - 9
SP - 526
EP - 542
JO - Anti-Cancer Agents in Medicinal Chemistry
JF - Anti-Cancer Agents in Medicinal Chemistry
SN - 1871-5206
IS - 5
ER -