Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast.
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.
Parsons
Ainslie B
AB
Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
Lopez
Andres
A
Givoni
Inmar E
IE
Williams
David E
DE
Gray
Christopher A
CA
Porter
Justin
J
Chua
Gordon
G
Sopko
Richelle
R
Brost
Renee L
RL
Ho
Cheuk-Hei
CH
Wang
Jiyi
J
Ketela
Troy
T
Brenner
Charles
C
Brill
Julie A
JA
Fernandez
G Esteban
GE
Lorenz
Todd C
TC
Payne
Gregory S
GS
Ishihara
Satoru
S
Ohya
Yoshikazu
Y
Andrews
Brenda
B
Hughes
Timothy R
TR
Frey
Brendan J
BJ
Graham
Todd R
TR
Andersen
Raymond J
RJ
Boone
Charles
C
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
D018931:Antineoplastic Agents, Hormonal; D000998:Antiviral Agents; D047630:Depsipeptides; D005656:Fungal Proteins; D004364:Pharmaceutical Preparations; D010718:Phosphatidylserines; C474171:papuamide B; D013629:Tamoxifen