Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3)
| Autor: | Ellen M. van Dam, Jack U. Flanagan, Hilary Brooks, Amanda Khoury, Colin K. W. Watts, William A. Denny, Marie Dziadek, Darby G. Brooke, Lisa-Jane K. Graham |
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| Rok vydání: | 2014 |
| Předmět: |
Fructose 1
6-bisphosphate Phosphofructokinase-2 Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Fructose 6-phosphate Antineoplastic Agents Chemistry Techniques Synthetic Biochemistry Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Drug Discovery Humans Bicinchoninic acid assay Glycolysis Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure Chemistry Organic Chemistry Warburg effect Molecular Docking Simulation Pyridazines Enzyme Fructose 2 6-bisphosphate Cancer cell Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:1029-1039 |
| ISSN: | 0968-0896 |
| Popis: | High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cells to generate ATP. A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition. Changes to the triazolo or pyridazinone rings were not favoured, but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme. Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway, as detected by a decrease in lactate production, but none of these compounds demonstrated such suppression at non-cytotoxic concentrations. |
| Databáze: | OpenAIRE |
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