Biochemistry Program

Figure 1. Methods like flow cytometry allow investigators to measure enzymes and substrates simultaneously (A) across millions of cancers cells (B) generating information-rich data-sets well suited for kinetic-analysis (C)

     To identify drugs that can overcome specific MDR-mechanisms, we will measure relative kinetic parameters (e.g. kcat, Km, IC50) for the most commonly used cancer-therapies in the clinic. These data sets will enable us to (1) more quantitatively define MDR-enzyme-substrate scope and (2) enable drug-repurposing by identifying drugs that are not susceptible Pgp-mediated resistance. Several critical features of our assay include:

  • Live-Cell Kinetic Measurements:   to directly compare drug-sensitivity to drug-efflux and maximize relevance of kinetic measurements to in vivo conditions (J. Biol. Chem. 2017, 292, 15838)
  • Multiple-Measurement & Single-cell Technologies:  to generate rich data-sets amenable to evaluation of complex kinetic mechanisms (Mol. Pharm. 1999, 56, 791)
  • Mathematical and Statistical Modeling to facilitate data-processing and fitting to multi-parameter kinetic models (Science, 2005, 308, 523)