|Title||Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast|
|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Parsons, 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|
|Type of Article||Article|
|Keywords||1, 3-BETA-D-GLUCAN SYNTHASE, BREAST-CANCER CELLS, DELETION MUTANTS, drug, EXPRESSION, GENOME-WIDE ANALYSIS, HAPLOINSUFFICIENCY, INDUCED, SACCHAROMYCES-CEREVISIAE, THEONELLA-SWINHOEI, TRANSCRIPTION FACTOR|
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.
|URL||<Go to ISI>://000239883400019|