ArticleJournal of medicinal chemistry2019
Tumor-Targeted Delivery of 6-Diazo-5-oxo-l-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs.
Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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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
42 citing papers in PubMed, 60 citations in OpenAlex.
- Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma.Journal of cellular physiology · 2026Review
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- Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Understanding and overcoming multidrug resistance in cancer.Nature reviews. Clinical oncology · 2025Review
- Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.Advanced biology · 2025Article
- Integrating Metabolic Modulation and Nanomedicine for Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
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- Metabolism, a Blossoming Target for Small-Molecule Anticancer Drugs.Molecules (Basel, Switzerland) · 2025Review
- Exploring the metabolic signaling network of GFPT in cancer.Cell death discovery · 2025Review
- Resilience and vulnerabilities of tumor cells under purine shortage stress.bioRxiv : the preprint server for biology · 2025Article
- A hormetic response model for glutamine stress in cancer.Trends in cancer · 2025Review
- Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs.Pharmaceutics · 2024Article
- Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.The Prostate · 2024Article
- Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.Acta pharmaceutica Sinica. B · 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
- Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.Nature cancer · 2024Article
- Discovery ofJournal of medicinal chemistry · 2023Article
- Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.Nature communications · 2023Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC
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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 OpenQuestion graph.