Unveiling both the effects and the targets of small molecules

It is hard to find good new drugs. Typically, new drug candidates are pursued either because they demonstrate affinity for a chosen molecule or “target,” or they alleviate certain symptoms of a disease. However, it would be best to pursue those candidates with both a well-understood mechanism of action as well as the desired biological effect. The difficulty lies in revealing both aspects early in the drug discovery process.

To that end, a team of scientists led by Stuart Schreiber, a founding member of the Broad Institute and the director of its Chemical Biology Program, developed an approach to eavesdrop on the molecular dialogue that transpires during drug treatment. Their work, reported January 15 in the online edition of Nature Chemical Biology, may provide a shortcut to expose the roots of drug action while selecting for drug effects.

The researchers established a collection of ~3900 modified yeast strains — each overexpressing a different gene — and used gene catalogs, called microarrays, to assess cell growth in the presence of the drug rapamycin. This drug, which is commonly given as an immunosuppressant following organ transplantation, has garnered recent interest as a potential cancer therapy. Using their approach, scientists could pinpoint genes that affect a cell’s susceptibility to rapamycin. These included known genes like TOR, a critical protein kinase and a well-known drug target, but also a host of new candidates that may be targeted by rapamycin and may function in a shared signaling network with TOR.

In a complementary analysis, the researchers studied LY-83583, a chemical that enables yeast to grow in the presence of rapamycin but whose mechanism of action is poorly understood. Among the genes that influence LY-83583 sensitivity, they discovered ones for mitochondrial proteins, suggesting that the compound exerts its effects by interfering with mitochondrial function. Broad scientists also noted that a common set of genes affects sensitivity to both rapamycin and its suppressor, LY-83583.

This work draws important mechanistic links between two compounds that are presumed to interact with TOR signals, a relay that regulates critical cellular functions in organisms ranging from yeast to humans. Furthermore, it implicates mitochondria as the possible gatekeepers of rapamycin sensitivity, which may help researchers to fully understand and harness the molecule’s therapeutic potential.

This approach can potentially be used for an almost unlimited range of cellular phenotypes and molecular entities.