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Cancer metabolism, DCA, dichloroacetate, PDC, PDK2 inhibitors, pyruvate.


National Institutes of Health. Netherlands Organization for Scientific Research. Dutch Ministry of Education, Culture and Science.


The Version of Scholarly Record of this Article is published in Journal of Enzyme Inhibition and Medicinal Chemistry 2016 available online at: DOI: 10.1080/14756366.2016.1201812


The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.


Medical Molecular Biology | Medical Sciences


Masini T, Birkaya B, van Dijk S, Mondal M, Hekelaar J, Jäger M, Terwisscha van Scheltinga AC, Patel MS, Hirsch AK, Moman E. Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;19:1-6 .

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