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

Tiziana Masini, Barbara Birkaya, Simon van Dijk, Milon Mondal, Johan Hekelaar, Manuel Jager, Anke C. Terwisscha van Scheltinga, Mulchand S. Patel, Anna K. H. Hirsch, Edelmiro Moman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)170-175
Number of pages6
JournalJournal of enzyme inhibition and medicinal chemistry
Volume31 (S4)
DOIs
Publication statusPublished - 2016

Keywords

  • Cancer metabolism
  • DCA
  • dichloroacetate
  • PDC
  • PDK2 inhibitors
  • pyruvate
  • CANCER-CELLS
  • METABOLISM
  • DICHLOROACETATE
  • MECHANISMS
  • PHOSPHORYLATION
  • HYPOXIA
  • COMPLEX

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