Unexpected Discovery of Dichloroacetate Derived Adenosine Triphosphate Competitors Targeting Pyruvate Dehydrogenase Kinase To Inhibit Cancer Proliferation

J Med Chem. 2016 Apr 14;59(7):3562-8. doi: 10.1021/acs.jmedchem.5b01828. Epub 2016 Mar 30.

Abstract

Pyruvate dehydrogenase kinases (PDKs) have recently emerged as an attractive target for cancer therapy. Herein, we prepared a series of compounds derived from dichloroacetate (DCA) which inhibited cancer cells proliferation. For the first time, we have successfully developed DCA derived inhibitors that preferentially bind to the adenosine triphosphate (ATP) pocket of PDK isoform 1 (PDK1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects*
  • Dichloroacetic Acid / chemistry*
  • Drug Discovery*
  • Female
  • Flow Cytometry
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Tumor Cells, Cultured

Substances

  • PDK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Adenosine Triphosphate
  • Dichloroacetic Acid
  • Protein Serine-Threonine Kinases