Peer Reviewed

1

Document Type

Article

Publication Date

19-7-2016

Keywords

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

Funder/Sponsor

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

Comments

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

Abstract

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.

Disciplines

Medical Molecular Biology | Medical Sciences

Citation

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 .

PubMed ID

27435185

DOI Link

10.1080/14756366.2016.1201812

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

Available for download on Wednesday, July 19, 2017

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