title: Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells.
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.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Yu
authors.forename: Andres
authors.initials: A
authors.lastname: Lopez
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Anaflous
authors.forename: Brahim
authors.initials: B
authors.lastname: El Bali
authors.forename: Abdellah
authors.initials: A
authors.lastname: Hamal
authors.forename: Elke
authors.initials: E
authors.lastname: Ericson
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Heisler
authors.forename: Angus
authors.initials: A
authors.lastname: McQuibban
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bellaoui
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000935:Antifungal Agents; D011725:Pyridines; D011743:Pyrimidines