Yu L~Bellaoui M, 2008

Pubmed ID 19043571
Title Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells.
Authors Lisa Yu, Andres Lopez, Abderrahmane Anaflous, Brahim El Bali, Abdellah Hamal, Elke Ericson, Lawrence E Heisler, Angus McQuibban, Guri Giaever, Corey Nislow, Charles Boone, Grant W Brown, Mohammed Bellaoui
Abstract Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical-genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure-activity relationships.
Citation PLoS Genet. 2008; 4:e1000284

Datasets

Download the list of datasets
Papers Phenotype Conditions Collection Tested mutants Data Details
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine [9 uM] hom 4,248 Quantitative
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine [9 uM] hap a 3,425 Quantitative
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine [9 uM] hom 4,248 Quantitative
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine [9 uM] hap a 3,425 Quantitative
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine [9 uM] het 1,006 Quantitative
Yu L~Bellaoui M, 2008 growth (relative abundance in pooled culture) 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine [9 uM] het 1,006 Quantitative

Curation history

Sept. 26, 2016 Tested strains to request.
Sept. 26, 2016 Data to request.
Sept. 29, 2016 Tested strains requested.
Sept. 29, 2016 Data requested.
Oct. 5, 2016 Tested strains to load.
Oct. 5, 2016 Data to load.
Feb. 1, 2017 Tested strains loaded.
Feb. 1, 2017 Data loaded.