Metabolomic high-content nuclear magnetic resonance-based drug screening of a kinase inhibitor library

Nat Commun. 2011 Nov 22;2:545. doi: 10.1038/ncomms1562.

Abstract

Metabolism is altered in many highly prevalent diseases and is controlled by a complex network of intracellular regulators. Monitoring cell metabolism during treatment is extremely valuable to investigate cellular response and treatment efficacy. Here we describe a nuclear magnetic resonance-based method for screening of the metabolomic response of drug-treated mammalian cells in a 96-well format. We validate the method using drugs having well-characterized targets and report the results of a screen of a kinase inhibitor library. Four hits are validated from their action on an important clinical parameter, the lactate to pyruvate ratio. An eEF-2 kinase inhibitor and an NF-kB activation inhibitor increased lactate/pyruvate ratio, whereas an MK2 inhibitor and an inhibitor of PKA, PKC and PKG induced a decrease. The method is validated in cell lines and in primary cancer cells, and may have potential applications in both drug development and personalized therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Magnetic Resonance Spectroscopy / methods*
  • Protein Kinase Inhibitors / analysis*

Substances

  • Protein Kinase Inhibitors