The primary objective of this proposal is to develop and deploy cutting edge technologies and chemical genomic tools and to understand the effects of small molecule inhibitors in vivo, and to characterize the model organism Saccharomyces cerevisiae on a systems level. Over the course of the past 3.5 years, as part of an NHGRI-funded project, we have applied three unique genome-wide screens to ~2,000 chemical inhibitors of growth. These data have led to several notable findings, including: 1) novel drug/target interactions, 2) a chemical phenotype for nearly all yeast genes, 3) a systems-level characterization of yeast, and 4) a better understanding of chemical structure-activity relationships as they manifest in vivo. These data have also guided the design of the next-generation chemical genomic assays proposed herein. Using our established bioinformatics and robotics infrastructure, we will design the next generation of assays to interrogate the genome's interaction with small molecules to unprecedented levels of scrutiny, while decreasing cost per chemical.

Public Health Relevance

Small molecules, the central focus of this proposal, make up the majority of FDA approved drugs. Unfortunately, the pharmaceutical industry is currently experiencing sky-rocketing costs (~800 million dollars per new drug) in addition to steadily decreasing productivity. These struggles are attributed in part to unforeseen side-effects of promising drug candidates and by a lack of validated cellular "targets" to which a drug can bind and elicit a medicinal effect.
The specific aims of this proposal address both of these problems.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG003317-08
Application #
8206671
Study Section
Special Emphasis Panel (ZRG1-GGG-T (90))
Program Officer
Ozenberger, Bradley
Project Start
2004-09-15
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$1,117,030
Indirect Cost
$299,804
Name
Stanford University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Nile, Aaron H; Tripathi, Ashutosh; Yuan, Peihua et al. (2014) PITPs as targets for selectively interfering with phosphoinositide signaling in cells. Nat Chem Biol 10:76-84
Schlecht, Ulrich; Suresh, Sundari; Xu, Weihong et al. (2014) A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system. BMC Genomics 15:263
Cokol, Murat; Weinstein, Zohar B; Yilancioglu, Kaan et al. (2014) Large-scale identification and analysis of suppressive drug interactions. Chem Biol 21:541-51
Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R et al. (2013) Miniature short hairpin RNA screens to characterize antiproliferative drugs. G3 (Bethesda) 3:1375-87
Blackman, Ronald K; Cheung-Ong, Kahlin; Gebbia, Marinella et al. (2012) Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. PLoS One 7:e29798
Tamble, Craig M; St Onge, Robert P; Giaever, Guri et al. (2011) The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae. Mol Biosyst 7:2019-30
Smith, Andrew M; Durbic, Tanja; Oh, Julia et al. (2011) Competitive genomic screens of barcoded yeast libraries. J Vis Exp :
Oh, Julia; Nislow, Corey (2011) Signature-tagged mutagenesis to characterize genes through competitive selection of bar-coded genome libraries. Methods Mol Biol 765:225-52
Oh, Julia; Fung, Eula; Schlecht, Ulrich et al. (2010) Gene annotation and drug target discovery in Candida albicans with a tagged transposon mutant collection. PLoS Pathog 6:e1001140
Smith, Andrew M; Ammar, Ron; Nislow, Corey et al. (2010) A survey of yeast genomic assays for drug and target discovery. Pharmacol Ther 127:156-64

Showing the most recent 10 out of 12 publications