title: Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.
abstract: 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.
authors.affiliation: Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck & Co, Inc, 12040 115th Avenue NE, Kirkland, WA 98034, USA. pek_lum@merck.com
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Armour
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Stepaniants
authors.forename: Guy
authors.initials: G
authors.lastname: Cavet
authors.forename: Maria K
authors.initials: MK
authors.lastname: Wolf
authors.forename: J Scott
authors.initials: JS
authors.lastname: Butler
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Hinshaw
authors.forename: Philippe
authors.initials: P
authors.lastname: Garnier
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Amy
authors.initials: A
authors.lastname: Leonardson
authors.forename: Philip
authors.initials: P
authors.lastname: Garrett-Engele
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rush
authors.forename: Martin
authors.initials: M
authors.lastname: Bard
authors.forename: Greg
authors.initials: G
authors.lastname: Schimmack
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Roberts
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Shoemaker
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D016681:Genome, Fungal; D006579:Heterozygote; D019751:Intramolecular Transferases / Q000187:drug effects / Q000378:metabolism; D008981:Molsidomine / Q000494:pharmacology; D011237:Predictive Value of Tests; D012335:RNA, Ribosomal / Q000187:drug effects / Q000378:metabolism; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D012335:RNA, Ribosomal; D008981:Molsidomine; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D005472:Fluorouracil