TOXI 141 |
| The organization of the biochemical networks of living cell can be defined by studying the dynamics of protein-protein interaction. Here we describe recent conceptual and experimental advances that can achieve this aim. We show how chemical perturbations of interactions can be used to identify off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. We use protein-fragment complementation assays (PCAs) to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. This strategy reproduced known structure-function relationships, and also predicted ‘hidden', potent antiproliferative activities for four drugs with novel mechanisms of action, including disruption of mitochondrial membrane potential. A simple algorithm identifies highly predictive assay panels and suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and potential toxicity. |
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Systems-wide Approaches to Understanding Drug Action and Toxicity
8:30 AM-12:00 PM, Thursday, August 23, 2007 BCEC -- 258C, Oral
Division of Chemical Toxicology |