Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast

Ainslie B Parsons; Andres Lopez; Inmar E Givoni; David E Williams; Christopher A Gray; Justin Porter; Gordon Chua; Richelle Sopko; Renee L Brost; Cheuk-Hei Ho; Jiyi Wang; Troy Ketela; Charles Brenner; Julie A Brill; G Esteban Fernandez; Todd C Lorenz; Gregory S Payne; Satoru Ishihara; Yoshikazu Ohya; Brenda Andrews; Timothy R Hughes; Brendan J Frey; Todd R Graham; Raymond J Andersen; Charles Boone

doi:10.1016/j.cell.2006.06.040

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Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast

Journal article

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Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast

Ainslie B Parsons, Andres Lopez, Inmar E Givoni, David E Williams, Christopher A Gray, Justin Porter, Gordon Chua, Richelle Sopko, Renee L Brost, Cheuk-Hei Ho, …

Cell, Vol.126(3), pp.611-625

08/11/2006

DOI: 10.1016/j.cell.2006.06.040

PMID: 16901791

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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.

Drug Evaluation, Preclinical - methods

Antiviral Agents - pharmacology

Antineoplastic Agents, Hormonal - pharmacology

Phosphatidylserines - metabolism

Pharmaceutical Preparations - classification

Fungal Proteins - drug effects

Gene Expression Profiling - methods

Depsipeptides - pharmacology

Signal Transduction - genetics

Fungal Proteins - genetics

Yeasts - drug effects

Mutation - genetics

Drug Resistance - genetics

Yeasts - genetics

Pharmaceutical Preparations - metabolism

Mutation - drug effects

Signal Transduction - drug effects

Pharmaceutical Preparations - chemistry

Tamoxifen - pharmacology

Molecular Structure

Cluster Analysis

Fungal Proteins - metabolism

Yeasts - metabolism

Details

Title: Subtitle: Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast
Creators: Ainslie B Parsons - Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada
Andres Lopez
Inmar E Givoni
David E Williams - University of British Columbia
Christopher A Gray
Justin Porter
Gordon Chua
Richelle Sopko
Renee L Brost
Cheuk-Hei Ho
Jiyi Wang
Troy Ketela
Charles Brenner
Julie A Brill
G Esteban Fernandez
Todd C Lorenz
Gregory S Payne
Satoru Ishihara
Yoshikazu Ohya
Brenda Andrews
Timothy R Hughes
Brendan J Frey
Todd R Graham
Raymond J Andersen
Charles Boone
Resource Type: Journal article
Publication Details: Cell, Vol.126(3), pp.611-625
DOI: 10.1016/j.cell.2006.06.040
PMID: 16901791
NLM abbreviation: Cell
ISSN: 0092-8674
eISSN: 1097-4172
Publisher: United States
Grant note: R01 CA075954-10 / NCI NIH HHS GM67911 / NIGMS NIH HHS GM72119 / NIGMS NIH HHS R01 CA075954 / NCI NIH HHS
Language: English
Date published: 08/11/2006
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788599402771

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