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

by: AB Parsons, A Lopez, IE Givoni, DE Williams, CA Gray, J Porter, G Chua, R Sopko, RL Brost, CH Ho, J Wang, T Ketela, C Brenner, JA Brill, GE Fernandez, TC Lorenz, GS Payne, S Ishihara, Y Ohya, B Andrews, TR Hughes, BJ Frey, TR Graham, RJ Andersen, C Boone

Cell, Vol. 126, No. 3. (11 August 2006), pp. 611-625.

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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.

@article{citeulike:851333, 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.}, address = {Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada.}, author = {Parsons, A. B. and Lopez, A. and Givoni, I. E. and Williams, D. E. and Gray, C. A. and Porter, J. and Chua, G. and Sopko, R. and Brost, R. L. and Ho, C. H. and Wang, J. and Ketela, T. and Brenner, C. and Brill, J. A. and Fernandez, G. E. and Lorenz, T. C. and Payne, G. S. and Ishihara, S. and Ohya, Y. and Andrews, B. and Hughes, T. R. and Frey, B. J. and Graham, T. R. and Andersen, R. J. and Boone, C. }, citeulike-article-id = {851333}, doi = {http://dx.doi.org/10.1016/j.cell.2006.06.040}, issn = {0092-8674}, journal = {Cell}, keywords = {chemical-genetics, yeast}, month = {August}, number = {3}, pages = {611--625}, posted-at = {2008-08-01 03:06:50}, priority = {2}, title = {Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast.}, url = {http://dx.doi.org/10.1016/j.cell.2006.06.040}, volume = {126}, year = {2006} }

RIS record

TY - JOUR ID - citeulike:851333 L3 - citeulike-article-id:851333 N2 - 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. IS - 3 JF - Cell SN - 0092-8674 AD - Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada. EP - 625 TI - Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast. VL - 126 SP - 611 KW - chemical-genetics KW - yeast AU - Parsons, AB AU - Lopez, A AU - Givoni, IE AU - Williams, DE AU - Gray, CA AU - Porter, J AU - Chua, G AU - Sopko, R AU - Brost, RL AU - Ho, CH AU - Wang, J AU - Ketela, T AU - Brenner, C AU - Brill, JA AU - Fernandez, GE AU - Lorenz, TC AU - Payne, GS AU - Ishihara, S AU - Ohya, Y AU - Andrews, B AU - Hughes, TR AU - Frey, BJ AU - Graham, TR AU - Andersen, RJ AU - Boone, C PY - 2006/08/11/ UR - http://dx.doi.org/10.1016/j.cell.2006.06.040 ER -

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