ArticleThe Journal of biological chemistry2018
Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 87 citations in OpenAlex.
- Article
- Review
- Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.International journal of molecular sciences · 2025Article
- A Cyanobacteria-Derived RNA Aptamer Resensitizes Prostate Cancer to Hormone Therapy.Cancer research · 2025Article
- Metabolic Adaptations in Cancer Progression: Optimization Strategies and Therapeutic Targets.Cancers · 2025Review
- l-[5-Acta pharmaceutica Sinica. B · 2025Article
- Innovative Strategies in X-ray Crystallography for Exploring Structural Dynamics and Reaction Mechanisms in Metabolic Disorders.Journal of personalized medicine · 2024Review
- Filament formation drives catalysis by glutaminase enzymes important in cancer progression.Nature communications · 2024Article
- Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.Cell communication and signaling : CCS · 2024Review
- Vessel co-option: a unique vascular-immune niche in liver cancer.Frontiers in oncology · 2024Review
- Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.Nature structural & molecular biology · 2023Article
- The immunometabolic ecosystem in cancer.Nature immunology · 2023Review
- The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review.Current issues in molecular biology · 2023Review
- Review
- The Metabolism and Immune Environment in Diffuse Large B-Cell Lymphoma.Metabolites · 2023Review
- Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.Nature communications · 2023Article
- The pyridazine heterocycle in molecular recognition and drug discovery.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2023Review
- Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.Future drug discovery · 2023Review
- Glutaminolysis and peripheral CD4Frontiers in immunology · 2023Review
- Serial Room Temperature Crystal Loading, Data Collection, and Data Processing of Human Glutaminase C in Complex with Allosteric Inhibitors.Bio-protocol · 2022Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Altered glycolytic flux in cancer cells (the "Warburg effect") causes their proliferation to rely upon elevated glutamine metabolism ("glutamine addiction"). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small molecule CB-839 was reported to be more potent than other allosteric GAC inhibitors, including the parent compound bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl (BPTES), and is in clinical trials. Recently, we described the synthesis of BPTES analogs having distinct saturated heterocyclic cores as a replacement for the flexible chain moiety, with improved microsomal stability relative to CB-839 and BPTES. Here, we show that one of these new compounds, UPGL00004, like CB-839, more potently inhibits the enzymatic activity of GAC, compared with BPTES. We also compare the abilities of UPGL00004, CB-839, and BPTES to directly bind to recombinant GAC and demonstrate that UPGL00004 has a similar binding affinity as CB-839 for GAC. We also show that UPGL00004 potently inhibits the growth of triple-negative breast cancer cells, as well as tumor growth when combined with the anti-vascular endothelial growth factor antibody bevacizumab. Finally, we compare the X-ray crystal structures for UPGL00004 and CB-839 bound to GAC, verifying that UPGL00004 occupies the same binding site as CB-839 or BPTES and that all three inhibitors regulate the enzymatic activity of GAC via a similar allosteric mechanism. These results provide insights regarding the potency of these inhibitors that will be useful in designing novel small-molecules that target a key enzyme in cancer cell metabolism.
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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.