ArticleInvestigational new drugs2018
Preclinical investigation of a potent geranylgeranyl diphosphate synthase inhibitor.
Article in Investigational new drugs, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Pharmacokinetics and Toxicity Assessment of Artesunate and Its Metabolite, Dihydroartemisinin, in NOD Scid Gamma Mice.Molecules (Basel, Switzerland) · 2026Article
- Incorporation of an alpha-hydroxy substituent modulates activity of triazole bisphosphonate-based geranylgeranyl diphosphate synthase inhibitors.Bioorganic & medicinal chemistry · 2026Article
- Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia (AML).Research square · 2025Article
- A somatic multiple myeloma mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS.The FEBS journal · 2025Article
- Structure-activity relationship of isoprenoid triazole bisphosphonate-based geranylgeranyl diphosphate synthase inhibitors: Effects on pharmacokinetics, biodistribution, and hepatic transporters.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity.JBMR plus · 2025Article
- Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma.Drug development research · 2023Article
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
- Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.Bioorganic & medicinal chemistry · 2021Article
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway.Pharmacological research · 2021Article
- Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors.Bioorganic & medicinal chemistry · 2020Article
- In Vivo Evaluation of Isoprenoid Triazole Bisphosphonate Inhibitors of Geranylgeranyl Diphosphate Synthase: Impact of Olefin Stereochemistry on Toxicity and Biodistribution.The Journal of pharmacology and experimental therapeutics · 2019Article
- ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors.Bioorganic & medicinal chemistry letters · 2019Article
- Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition.Cell death & disease · 2019Article
- Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma.Oncogene · 2019Article
- Simultaneous Quantitation of Isoprenoid Pyrophosphates in Plasma and Cancer Cells Using LC-MS/MS.Molecules (Basel, Switzerland) · 2018Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Geranylgeranyl diphosphate synthase (GGDPS) is the enzyme in the isoprenoid biosynthesis pathway that catalyzes the synthesis of the 20-carbon isoprenoid GGPP, which serves as the isoprenoid donor for protein geranylgeranylation reactions. Rab proteins mediate vesicle trafficking within the cell and their activity is dependent on geranylgeranylation. Our prior work has demonstrated that agents that disrupt Rab geranylgeranylation disrupt monoclonal protein trafficking in myeloma cells, resulting in induction of the unfolded protein response pathway and apoptosis. VSW1198 is a potent GGDPS inhibitor with measurable cellular activity at concentrations as low as 30 nM. Due to its potent activity against myeloma cells in vitro, we were interested in evaluating the toxicology profile, pharmacokinetic (PK) profile, tissue distribution pattern and metabolic stability of VSW1198 in preparation for in vivo efficacy studies. Single dose testing via IV administration in CD-1 mice revealed a maximum tolerated dose of 0.5 mg/kg. Doses ≥1 mg/kg resulted in liver toxicity that peaked around 6-7 days post-injection. Disruption of protein geranylgeranylation following repeat dosing of VSW1198 was confirmed via immunoblot analysis of unmodified Rap1a in multiple organs. The PK studies revealed a half-life of 47.7 ± 7.4 h. VSW1198 was present in all tested tissues with the highest levels in the liver. In both human liver microsomes and mouse S9 studies VSW1198 showed complete stability, suggesting no phase I or phase II metabolism. In summary, these studies demonstrate systemic distribution, on-target disruption of protein geranylgeranylation, and metabolic stability of a potent GGDPS inhibitor VSW1198 and form the basis for future efficacy studies in mouse models of myeloma.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.