ArticleClinical cancer research : an official journal of the American Association for Cancer Research2010
Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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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
58 citing papers in PubMed, 2 syntheses or guidelines pooled it, 128 citations in OpenAlex.
- Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.Frontiers in oncology · 2021Pooled it
- Metabolite Profiling in Anticancer Drug Development: A Systematic Review.Drug design, development and therapy · 2020Pooled it
- Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.JCI insight · 2018Trial
- Review
- (Oxidopyridyl)Porphyrins of Different Lipophilicity: Photophysical Properties, ROS Production and Phototoxicity on Melanoma Cells Under CoClAntioxidants (Basel, Switzerland) · 2025Article
- Coenzyme QMolecules (Basel, Switzerland) · 2025Article
- Medicinal Chemistry of Drugs withJournal of medicinal chemistry · 2024Review
- Introducing urea into tirapazamine derivatives to enhance anticancer therapy.National science review · 2024Article
- Review
- Spin Trapping Hydroxyl and Aryl Radicals of One-Electron Reduced Anticancer Benzotriazine 1,4-Dioxides.Molecules (Basel, Switzerland) · 2022Article
- Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.Frontiers in pharmacology · 2022Article
- Therapeutic targeting of the hypoxic tumour microenvironment.Nature reviews. Clinical oncology · 2021Review
- Synthesis of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: a way forward for targeting hypoxia and drug resistance of cancer cells.RSC advances · 2021Article
- EnamineACS central science · 2021Article
- Glioma stem cells and their roles within the hypoxic tumor microenvironment.Theranostics · 2021Review
- Subcellular Location of Tirapazamine Reduction Dramatically Affects Aerobic but Not Anoxic Cytotoxicity.Molecules (Basel, Switzerland) · 2020Article
- Three dimensional engineered models to study hypoxia biology in breast cancer.Cancer letters · 2020Review
- Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity.International journal of molecular sciences · 2019Article
- Article
- Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors.Molecules (Basel, Switzerland) · 2019Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeTirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization. EXPERIMENTAL
designThe SR-PKPD model was used to guide the progression of 281 TPZ analogues through a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single-cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, diffusion coefficients in multicellular layers, and plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation.
resultsSR-PKPD-guided lead optimization identified SN29751 and SN30000 as the most promising hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor cell cultures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts.
conclusionsSN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development.
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What OpenQuestion holds
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.