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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.

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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

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