We have analyzed over 100 FDA approved compounds using an approach
that combines whole-genome fitness testing and expression analysis to
identify drug targets. A highly parallel fitness assay was used to
screen a large collection of bar-coded heterozygotes for drug induced
haploinsufficiency. Previous work has shown that heterozygotes that
are hypersensitive to a given compound often correspond to the
compound's target (Nature Genetics 1999 Mar 21:3 p. 278-83). A
novel two-color fitness assay that uses custom ink-jet arrays has been
developed to measure the growth rates for each of the tagged deletion
strains in the pool. Our current deletion pool contains over 4,500
bar-coded strains that were generated by the Yeast Deletion Project
(Science 1999 Aug 6 285:5429 901-6). Each of the 100 FDA
compounds were also analyzed using the Genome Reporter Matrix which
consists of a collection of reporter gene fusions to >95% of the yeast
genes. The mode of action of a compound can be determined by comparing
its expression profile against a reference library containing
thousands of drug treatments and mutant profiles. Several examples
will be presented to illustrate the power of our integrated genomics
approach for identifying drug targets.
Return to YGM 2000 Abstract Index