In Vivo Evaluation of Isoprenoid Triazole Bisphosphonate Inhibitors of Geranylgeranyl Diphosphate Synthase: Impact of Olefin Stereochemistry on Toxicity and Biodistribution.
Alkenes
/ chemistry
Animals
Diphosphonates
/ chemistry
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
/ methods
Farnesyltranstransferase
/ antagonists & inhibitors
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Microsomes, Liver
/ drug effects
Stereoisomerism
Terpenes
/ chemistry
Tissue Distribution
/ drug effects
Triazoles
/ chemistry
Xenograft Model Antitumor Assays
/ methods
Journal
The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
04
04
2019
accepted:
15
08
2019
pubmed:
20
8
2019
medline:
25
4
2020
entrez:
18
8
2019
Statut:
ppublish
Résumé
The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the
Identifiants
pubmed: 31420526
pii: jpet.119.258624
doi: 10.1124/jpet.119.258624
pmc: PMC6795743
doi:
Substances chimiques
Alkenes
0
Diphosphonates
0
Terpenes
0
Triazoles
0
Farnesyltranstransferase
EC 2.5.1.29
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
327-338Subventions
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172070
Pays : United States
Informations de copyright
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
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