Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 May 27;22(6):886.
doi: 10.3390/molecules22060886.

Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors

Staci L Haney  1 , Veronica S Wills  2 , David F Wiemer  3 , Sarah A Holstein  4
Affiliations
Review

Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors

Staci L Haney et al. Molecules. .

Abstract

The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs.

Keywords: geranylgeranyl diphosphate synthase; geranylgeranylation; inhibitors; isoprenoid.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): D.F.W. is a named inventor of intellectual property related to digeranyl bisphosphonate that is owned by the University of Iowa Research Foundation. He is a founder of Terpenoid Therapeutics, Inc., which has licensed this property.

Figures

Figure 1
Figure 1
The mammalian isoprenoid biosynthetic pathway with associated inhibitors.
Figure 2
Figure 2
Chemical structures of select geranylgeranyl diphosphate synthase (GGDPS) inhibitors.
Figure 3
Figure 3
Synthetic sequences to dialkyl (17) and alkyl/alkoxy (22) bisphosphonates.
Figure 4
Figure 4
A convergent synthesis to triazole bisphosphonates.
Figure 5
Figure 5
Stereoselective synthesis of isoprenoid triazole bisphosphonates through the use of epoxy azides [39].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Guo Z., Wu Y.W., Das D., Delon C., Cramer J., Yu S., Thuns S., Lupilova N., Waldmann H., Brunsveld L., et al. Structures of RabGGTase-substrate/product complexes provide insights into the evolution of protein prenylation. EMBO J. 2008;27:2444–2456. doi: 10.1038/emboj.2008.164. - DOI - PMC - PubMed
    1. Gomes A.Q., Ali B.R., Ramalho J.S., Godfrey R.F., Barral D.C., Hume A.N., Seabra M.C. Membrane targeting of Rab GTPases is influenced by the prenylation motif. Mol. Biol. Cell. 2003;14:1882–1899. doi: 10.1091/mbc.E02-10-0639. - DOI - PMC - PubMed
    1. Chao Y.S., Kroon P.A., Yamin T.T., Thompson G.M., Alberts A.W. Regulation of hepatic receptor-dependent degradation of LDL by mevinolin in rabbits with hypercholesterolemia induced by a wheat starch-casein diet. Biochim. Biophys. Acta. 1983;754:134–141. doi: 10.1016/0005-2760(83)90154-6. - DOI - PubMed
    1. Bilheimer D.W., Grundy S.M., Brown M.S., Goldstein J.L. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc. Natl. Acad. Sci. USA. 1983;80:4124–4128. doi: 10.1073/pnas.80.13.4124. - DOI - PMC - PubMed
    1. Zhou Q., Liao J.K. Pleiotropic effects of statins.—Basic research and clinical perspectives. Circ. J. 2010;74:818–826. doi: 10.1253/circj.CJ-10-0110. - DOI - PMC - PubMed

MeSH terms