title: Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast.
abstract: Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of "chemical-genetic interaction" profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular pathways and proteins affected, we applied both a hierarchical clustering and a factorgram method, which allows a gene or compound to be associated with more than one group. In particular, tamoxifen, a breast cancer therapeutic, was found to disrupt calcium homeostasis and phosphatidylserine (PS) was recognized as a target for papuamide B, a cytotoxic lipopeptide with anti-HIV activity. Further, the profile of crude extracts resembled that of its constituent purified natural product, enabling detailed classification of extract activity prior to purification. This compendium should serve as a valuable key for interpreting cellular effects of novel compounds with similar activities.
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
authors.forename: Ainslie B
authors.initials: AB
authors.lastname: Parsons
authors.forename: Andres
authors.initials: A
authors.lastname: Lopez
authors.forename: Inmar E
authors.initials: IE
authors.lastname: Givoni
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gray
authors.forename: Justin
authors.initials: J
authors.lastname: Porter
authors.forename: Gordon
authors.initials: G
authors.lastname: Chua
authors.forename: Richelle
authors.initials: R
authors.lastname: Sopko
authors.forename: Renee L
authors.initials: RL
authors.lastname: Brost
authors.forename: Cheuk-Hei
authors.initials: CH
authors.lastname: Ho
authors.forename: Jiyi
authors.initials: J
authors.lastname: Wang
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.forename: Charles
authors.initials: C
authors.lastname: Brenner
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brill
authors.forename: G Esteban
authors.initials: GE
authors.lastname: Fernandez
authors.forename: Todd C
authors.initials: TC
authors.lastname: Lorenz
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Payne
authors.forename: Satoru
authors.initials: S
authors.lastname: Ishihara
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohya
authors.forename: Brenda
authors.initials: B
authors.lastname: Andrews
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
authors.forename: Todd R
authors.initials: TR
authors.lastname: Graham
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D016000:Cluster Analysis; D047630:Depsipeptides / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004351:Drug Resistance / Q000235:genetics*; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D015394:Molecular Structure; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D015003:Yeasts / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000998:Antiviral Agents; D047630:Depsipeptides; D005656:Fungal Proteins; D004364:Pharmaceutical Preparations; D010718:Phosphatidylserines; C474171:papuamide B; D013629:Tamoxifen