Pek Yee Lum,^1,6 Christopher D. Armour,^1,6 Sergey B. Stepaniants,¹ Guy Cavet,¹ Maria K. Wolf,³ J. Scott Butler,³ Jerald C. Hinshaw,⁵ Philippe Garnier,⁵ Glenn D. Prestwich,⁵ Amy Leonardson,1 Philip Garrett-Engele,¹ Christopher M. Rush,4 Martin Bard,⁴ Greg Schimmack,1 John W. Phillips,² Christopher J. Roberts,¹ and Daniel D. Shoemaker¹

¹Rosetta Inpharmatics LLC, a wholly-owned supsidiary of Merck & Co., Inc., 12040 115th Avenue N.E., Kirkland, WA 98034 USA
²Merck & Co., Inc., 126 East Lincoln Avenue, R80Y-255, Rahway, NJ 07065 USA
³Department of Microbiology and Immunology, J.P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642 USA
⁴Department of Biology, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN 46202 USA
⁵Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108 USA

 

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.