Drug Target Strategies

An intergenerational approach to identifications of mechanism of action and drug targets

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  Wei Zheng, PhD

  Group Leader
  National Center for Advancing Translational Sciences, National Institutes of Health

An intergenerational approach to identifications of mechanism of action and drug targets.
Wei Zheng
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
High quality lead compounds can be found from the phenotypical screening, especially in the screens for drug repurposing. But the mechanisms of action and drug targets for these lead compounds are usually unknown. It is a challenge to work on the target identification and to study the mechanism of action for a lead compound. We have recently employed two platform technologies to unlock drug-target engagement including the Drug Affinity Responsive Target Stability (DARTS) with proteomics by mass spectrometry and Cellular Thermal Shift Assay (CETSA) using target specific antibodies. Both methods use the native proteins in cells to determine the binding of a drug to its target protein, which results in physiologically relevant binding affinity of drug with its target protein. Via an integration of these methods, we have identified the AMPK beta-subunit as a drug target for beta-cyclodextrin which allosterically activates AMPK and autophagy. We also identified three potential targets for Torin-2 which potently suppresses malarial gametocytes. Additional examples of target identification using these methods will be overviewed and discussed. Therefore, this integrational approach with DARTS and CETSA can be broadly used for identification of new drug targets.