Journal
CELL
Volume 116, Issue 1, Pages 121-137Publisher
CELL PRESS
DOI: 10.1016/S0092-8674(03)01035-3
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Funding
- NCI NIH HHS [R01 CA095913, CA95913] Funding Source: Medline
- NIGMS NIH HHS [GM59898, GM62104, R01 GM059898, GM44836] Funding Source: Medline
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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 molsi- domine, 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.
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