Article abstract
Nature Chemical Biology 2, 329 - 337 (2006)
Published online: 7 May 2006 | doi:10.1038/nchembio790
Identifying off-target effects and hidden phenotypes of drugs in human cells
Marnie L MacDonald1, Jane Lamerdin1, Stephen Owens1, Brigitte H Keon1, Graham K Bilter1, Zhidi Shang1, Zhengping Huang1, Helen Yu1, Jennifer Dias1, Tomoe Minami1, Stephen W Michnick2 & John K Westwick1
Abstract
We present a strategy for identifying off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. High-content protein-fragment complementation assays (PCAs) were constructed with synthetic fragments of a mutant fluorescent protein ('Venus', EYFP or both), allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. One hundred and seven different drugs from six therapeutic areas were screened against 49 different PCA reporters for ten cellular processes. 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 identified a 25-assay panel that was highly predictive of antiproliferative activity, and the predictive power of this approach was confirmed with cross-validation tests. This study suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and thereby enhances the productivity of drug-discovery research.
- Odyssey Thera, Inc. 4550 Norris Canyon Rd. Suite 140, San Ramon, California 94583, USA.
- Département de Biochimie Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, Quebec H3C 3J7, Canada.
Correspondence to: Stephen W Michnick2 e-mail: stephen.michnick@umontreal.ca
Correspondence to: John K Westwick1 e-mail: jwestwick@odysseythera.com
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