In a new study in Nature, researchers at the University of California, San Francisco, teamed up with researchers at Mount Sinai School of Medicine in New York to develop a new technique for phenotypic screening for drug compounds. Doing phenotypic screening right isn't easy, says In the Pipeline's Derek Lowe, especially when a so-called targeted drug hits more than one target along the way. The study's authors used fruit flies to screen a variety of kinase inhibitors while also checking the compounds against a list of kinase enzymes. "This gives you a chance to do something that you don't often get a chance to do: match one kind of fingerprint to another kind," Lowe says. "And what they found was that you needed 'balanced polypharmacology' to get optimal phenotypic effects."
The researchers found that compounds that inhibited several genes in Drosophila were optimal, but found that several similar compounds were less effective because they affected one additional gene. "Working these combinations out was not trivial — it took a lot of different strains of flies with different levels of kinase activity, and a lot of different compounds with varying profiles," Lowe adds.