A new motif for inhibitors of geranylgeranyl diphosphate synthase

Benjamin J. Foust, Cheryl Allen, Sarah A. Holstein, David F. Wiemer

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure–function relationship which is dependent on the nature of the alkyl group at the α-carbon.

Original languageEnglish (US)
Pages (from-to)3734-3741
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number16
StatePublished - 2016
Externally publishedYes


  • Bisphosphonate monoester
  • GGDP synthase
  • Inhibition
  • Isoprenoid biosynthesis
  • Prodrug

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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