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.
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.
|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|
|Lee, Anna Y; St Onge, Robert P; Proctor, Michael J et al. (2014) Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344:208-11|
|Aiyar, Raeka S; Bohnert, Maria; Duvezin-Caubet, StÃ©phane et al. (2014) Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders. Nat Commun 5:5585|
|Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R et al. (2013) Miniature short hairpin RNA screens to characterize antiproliferative drugs. G3 (Bethesda) 3:1375-87|
|St Onge, Robert; Schlecht, Ulrich; Scharfe, Curt et al. (2012) Forward chemical genetics in yeast for discovery of chemical probes targeting metabolism. Molecules 17:13098-115|
|Wu, Manhong; Zheng, Ming; Zhang, Weiruo et al. (2012) Identification of drug targets by chemogenomic and metabolomic profiling in yeast. Pharmacogenet Genomics 22:877-86|
|Douglas, Alison C; Smith, Andrew M; Sharifpoor, Sara et al. (2012) Functional analysis with a barcoder yeast gene overexpression system. G3 (Bethesda) 2:1279-89|
|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|
Showing the most recent 10 out of 19 publications