Logo image
Back
Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase
Journal article   Open access   Peer reviewed

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Cheryl Allen, Sandhya Kortagere, Huaxiang Tong, Robert A Matthiesen, Joseph I Metzger, David F Wiemer and Sarah A Holstein
Molecular pharmacology, v 91(3), pp 229-236
Mar 2017
DOI: https://doi.org/10.1124/mol.116.107326
PMID: 28057800
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1124/mol.116.107326View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Catalytic Domain Cell Line, Tumor Diphosphonates - chemistry Diphosphonates - pharmacology Drug Synergism Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Farnesyltranstransferase - antagonists & inhibitors Farnesyltranstransferase - chemistry Farnesyltranstransferase - metabolism Humans Isomerism Lovastatin - pharmacology Models, Molecular Polyisoprenyl Phosphates - metabolism Sesquiterpenes - metabolism Triazoles - chemistry Triazoles - pharmacology
The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We reported a series of triazole bisphosphonate GGDPS inhibitors, of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers. Here we determined the activity of the individual olefin isomers. Enzymatic and cellular assays revealed that although HN is approximately threefold more potent than HG, HN is not more potent than the original mixture. Studies in which cells were treated with varying concentrations of each isomer alone and in different combinations revealed that the two isomers potentiate the induced-inhibition of protein geranylgeranylation when used in a 3:1 HG:HN combination. A synergistic interaction was observed between the two isomers in the GGDPS enzyme assay. These results suggested that the two isomers bind simultaneously to the enzyme but within different domains. Computational modeling studies revealed that HN is preferred at the FDP site, that HG is preferred at the GGDP site, and that both isomers may bind to the enzyme simultaneously. These studies are the first to report a set of olefin isomers that synergistically inhibit GGDPS, thus establishing a new paradigm for the future development of GGDPS inhibitors.

Metrics

6 Record Views
21 citations in Web of Science
20 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
Web of Science research areas
Pharmacology & Pharmacy
Logo image