title: Identifying off-target effects and hidden phenotypes of drugs in human cells.
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.
authors: Odyssey Thera, Inc. 4550 Norris Canyon Rd. Suite 140, San Ramon, California 94583, USA.
authors: Marnie L
authors: ML
authors: MacDonald
authors: Jane
authors: J
authors: Lamerdin
authors: Stephen
authors: S
authors: Owens
authors: Brigitte H
authors: BH
authors: Keon
authors: Graham K
authors: GK
authors: Bilter
authors: Zhidi
authors: Z
authors: Shang
authors: Zhengping
authors: Z
authors: Huang
authors: Helen
authors: H
authors: Yu
authors: Jennifer
authors: J
authors: Dias
authors: Tomoe
authors: T
authors: Minami
authors: Stephen W
authors: SW
authors: Michnick
authors: John K
authors: JK
authors: Westwick