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

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.

Keywords:

• Cancer metabolism
• DCA
• dichloroacetate
• PDC
• PDK2 inhibitors
• pyruvate

Declaration of interest

The authors declare no competing financial interest. This work has received funding from the National Institutes of Health (M.S.P.) the Netherlands Organization for Scientific Research (A.K.H.H.) and the Dutch Ministry of Education, Culture and Science (A.K.H.H.). The National Institutes of Health (NIH) is acknowledged for Grant DK20478 to M.S.P. The Netherlands Organization for Scientific Research is acknowledged for Grant NWO-CW, ECHO-STIP to A.K.H.H. The Dutch Ministry of Education, Culture and Science for Gravitation Program Grant 024.001.035 to A.K.H.H.

Supplementary material available online