Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.
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.
Lum
Pek Yee
PY
Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck & Co, Inc, 12040 115th Avenue NE, Kirkland, WA 98034, USA. pek_lum@merck.com
Armour
Christopher D
CD
Stepaniants
Sergey B
SB
Cavet
Guy
G
Wolf
Maria K
MK
Butler
J Scott
JS
Hinshaw
Jerald C
JC
Garnier
Philippe
P
Prestwich
Glenn D
GD
Leonardson
Amy
A
Garrett-Engele
Philip
P
Rush
Christopher M
CM
Bard
Martin
M
Schimmack
Greg
G
Phillips
John W
JW
Roberts
Christopher J
CJ
Shoemaker
Daniel D
DD
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
D012335:RNA, Ribosomal; D008981:Molsidomine; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D005472:Fluorouracil