ArticleJournal of neuropathology and experimental neurology2021
Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis.
Article in Journal of neuropathology and experimental neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Molecular mechanisms and targeted therapeutic strategies for glycolytic reprogramming in osteosarcoma.Genes & diseases · 2027Review
- Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.Cancer treatment and research · 2026Review
- Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.Current cancer drug targets · 2026Review
- Exploring the metabolic signaling network of GFPT in cancer.Cell death discovery · 2025Review
- Glutamine's double-edged sword: fueling tumor growth and offering therapeutic hope.Frontiers in immunology · 2025Review
- Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines.International journal of molecular sciences · 2024Article
- Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.Journal of endocrinological investigation · 2024Article
- Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.Nature cancer · 2024Article
- Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.Frontiers in pharmacology · 2024Review
- Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor.Molecular cancer therapeutics · 2023Article
- Review
- Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.Future drug discovery · 2023Review
- Overview of Cancer Metabolism and Signaling Transduction.International journal of molecular sciences · 2022Review
- Metabolic determinants of stemness in medulloblastoma.World journal of stem cells · 2022Review
- Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma.Frontiers in cell and developmental biology · 2022Review
- Glutamine Antagonist GA-607 Causes a Dramatic Accumulation of FGAR which can be used to Monitor Target Engagement.Current drug metabolism · 2021Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.
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