ArticleJournal of the American Chemical Society2015
Identification of fumarate hydratase inhibitors with nutrient-dependent cytotoxicity.
Article in Journal of the American Chemical Society, 2015. 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, 35 citations in OpenAlex.
- Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.Current oncology (Toronto, Ont.) · 2026Review
- BCL-XbioRxiv : the preprint server for biology · 2025Article
- Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies.Aging and disease · 2025Review
- Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.Nature microbiology · 2025Article
- Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.Journal of inflammation research · 2025Article
- Review
- Target identification of small molecules: an overview of the current applications in drug discovery.BMC biotechnology · 2023Review
- Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.Basic research in cardiology · 2023Review
- Rutaecarpine induces the differentiation of triple-negative breast cancer cells through inhibiting fumarate hydratase.Journal of translational medicine · 2023Article
- Article
- Basic Mechanisms of Immunometabolites in Shaping the Immune Response.Journal of innate immunity · 2023Review
- Multiple Bioinformatics Analyses of Integrated Gene Expression Profiling Data and Verification of Hub Genes Associated with Diabetic Retinopathy.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Identification of Activators of Human Fumarate Hydratase by Quantitative High-Throughput Screening.SLAS discovery : advancing life sciences R & D · 2020Article
- Targeting of Fumarate Hydratase fromJournal of medicinal chemistry · 2019Article
- Diverse Stakeholders of Tumor Metabolism: An Appraisal of the Emerging Approach of Multifaceted Metabolic Targeting by 3-Bromopyruvate.Frontiers in pharmacology · 2019Review
- Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Development of cell-permeable small molecules that target enzymes involved in energy metabolism remains important yet challenging. We describe here the discovery of a new class of compounds with a nutrient-dependent cytotoxicity profile that arises from pharmacological inhibition of fumarate hydratase (also known as fumarase). This finding was enabled by a high-throughput screen of a diverse chemical library in a panel of human cancer cell lines cultured under different growth conditions, followed by subsequent structure-activity optimization and target identification. While the highest cytotoxicity was observed under low glucose concentrations, the antiproliferative activities and inhibition of oxygen consumption rates in cells were distinctly different from those displayed by typical inhibitors of mitochondrial oxidative phosphorylation. The use of a photoaffinity labeling strategy identified fumarate hydratase as the principal pharmacological target. Final biochemical studies confirmed dose-dependent, competitive inhibition of this enzyme in vitro, which was fully consistent with the initially observed growth inhibitory activity. Our work demonstrates how the phenotypic observations combined with a successful target identification strategy can yield a useful class of pharmacological inhibitors of an enzyme involved in the operation of tricarboxylic acid cycle.
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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.