Discovering Modes of Action for Therapeutic Compounds Using a Genome-Wide Screen of Yeast Heterozygotes

Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design...

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Bibliographic Details
Published in:Cell 2004-01, Vol.116 (1), p.121-137
Main Authors: Lum, Pek Yee, Armour, Christopher D., Stepaniants, Sergey B., Cavet, Guy, Wolf, Maria K., Butler, J.Scott, Hinshaw, Jerald C., Garnier, Philippe, Prestwich, Glenn D., Leonardson, Amy, Garrett-Engele, Philip, Rush, Christopher M., Bard, Martin, Schimmack, Greg, Phillips, John W., Roberts, Christopher J., Shoemaker, Daniel D.
Format: Article
Language:English
Subjects:
Drug Evaluation, Preclinical - methods
exosomes
Fluorouracil - pharmacology
Gene Expression Profiling - methods
Genome, Fungal
Heterozygote
Intramolecular Transferases - drug effects
Intramolecular Transferases - metabolism
molsidomine
Molsidomine - pharmacology
Predictive Value of Tests
Reproducibility of Results
RNA, Ribosomal - drug effects
RNA, Ribosomal - metabolism
Saccharomyces cerevisiae
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
sterols
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Summary:Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(03)01035-3