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

TitleExploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast
Publication TypeJournal Article
Year of Publication2006
AuthorsParsons, AB, Lopez, A, Givoni, IE, Williams, DE, Gray, CA, Porter, J, Chua, G, Sopko, R, Brost, RL, Ho, CH, Wang, JY, Ketela, T, Brenner, C, Brill, JA, Fernandez, GE, Lorenz, TC, Payne, GS, Ishihara, S, Ohya, Y, Andrews, B, Hughes, TR, Frey, BJ, Graham, TR, Andersen, RJ, Boone, C
JournalCell
Volume126
Pagination611-625
Date PublishedAug
Type of ArticleArticle
ISBN Number0092-8674
Keywords1, 3-BETA-D-GLUCAN SYNTHASE, BREAST-CANCER CELLS, DELETION MUTANTS, drug, EXPRESSION, GENOME-WIDE ANALYSIS, HAPLOINSUFFICIENCY, INDUCED, SACCHAROMYCES-CEREVISIAE, THEONELLA-SWINHOEI, TRANSCRIPTION FACTOR
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.

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