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Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.

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posted on 22.11.2019 by Tiziana Masini, Barbara Birkaya, Simon van Dijk, Milon Mondal, Johan Hekelaar, Manuel Jäger, Anke C. Terwisscha van Scheltinga, Mulchand S. Patel, Anna KH Hirsch, Edelmiro Moman

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.

Funding

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

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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

Published 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 .

Publication Date

19/07/2016

Publisher

Taylor & Francis Group

PubMed ID

27435185

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