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


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.

SUBMITTER: Tiziani S 

PROVIDER: S-EPMC5529142 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Tiziani Stefano S   Kang Yunyi Y   Choi Janet S JS   Roberts William W   Paternostro Giovanni G  

Nature communications 20111122


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 met  ...[more]

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