ArticleOncogene2019
Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma.
Article in Oncogene, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 35 citations in OpenAlex.
- Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Incorporation of an alpha-hydroxy substituent modulates activity of triazole bisphosphonate-based geranylgeranyl diphosphate synthase inhibitors.Bioorganic & medicinal chemistry · 2026Article
- Mevalonate pathway in pancreatic ductal adenocarcinoma: Mechanisms driving metabolic and cellular plasticity.Cancer pathogenesis and therapy · 2026Review
- Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.Bioorganic & medicinal chemistry · 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
- Targeting the mevalonate pathway enhances the efficacy of 5-fluorouracil by regulating pyroptosis.Medical oncology (Northwood, London, England) · 2024Article
- SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma.Cancer research communications · 2024Article
- Inhibition of human mevalonate kinase by allosteric inhibitors of farnesyl pyrophosphate synthase.FEBS open bio · 2024Article
- In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency.Molecular metabolism · 2024Article
- Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy.Molecular cancer therapeutics · 2024Review
- Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer.Journal of medicinal chemistry · 2023Article
- 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
- Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma.International journal of molecular sciences · 2022Review
- Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma.Metabolites · 2022Article
- 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
- The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease.The Journal of biological chemistry · 2020Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded protein response pathway (UPR) and apoptosis. To this end, we evaluated the effects of RAM2061, a potent GGDPSi, against PDAC. Our studies revealed that GGDPSi treatment activates the UPR and triggers apoptosis in a variety of human and mouse PDAC cell lines. Furthermore, GGDPSi treatment was found to disrupt the intracellular trafficking of key mucins such as MUC1. These effects could be recapitulated by incubation with a specific GGTase II inhibitor, but not a GGTase I inhibitor, consistent with the effect being dependent on disruption of Rab-mediated activities. In addition, siRNA-mediated knockdown of GGDPS induces upregulation of UPR markers and disrupts MUC1 trafficking in PDAC cells. Experiments in two mouse models of PDAC demonstrated that GGDPSi treatment significantly slows tumor growth. Collectively, these data support further development of GGDPSi therapy as a novel strategy for the treatment of PDAC.
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Registered trials
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.