Lee, A.Y. et al. Science 344, 208–211 (2014).

Small molecules are useful tools for probing protein function in cells. Lee et al. report a large-scale screen characterizing the cellular response of yeast to a panel of 3,250 growth-inhibiting small molecules. They used a profiling approach called HIPHOP (haploinsufficiency profiling and homozygous profiling) to identify the protein targets of a small molecule by measuring fitness defects in a large number of heterozygous strains representing the essential genome and in an even larger number of homozygous deletion strains to identify non-essential genes that mitigate the effects of the small molecule. They identified 317 compounds that specifically affected the function of 121 genes. The yeast cells responded to the small molecules in just 45 different ways, which the researchers refer to as chemogenomic signatures. Lee et al. hypothesize that similar small-molecule response systems may be present across eukaryotic cells.