A new tool to probe the shuttling of proteins through different parts of the cell comes in the form of the small molecule secramine A (shown). Tomas Kirchhausen, Matthew D. Shair, and Henry E. Pelish of Harvard University and collaborators have shown that this molecule, discovered through diversity-oriented synthesis and phenotypic screening, inhibits protein traffic out of the Golgi apparatus, the organelle in which proteins are processed after they are synthesized in the endoplasmic reticulum (Nature Chem. Biol., published Nov. 20, dx.doi.org/10.1038/nchembio751). Secramine A causes the membrane protein Cdc42 to dissociate from membranes, thereby rendering it unable to activate other proteins that it normally activates. The researchers also used secramine A to study other processes involving Cdc42, such as reorientation of the Golgi apparatus during cell migration. “Our results underscore the usefulness of combining high-throughput synthesis, phenotypic screening, and target identification for discovering cell-permeable small molecules that perturb biological systems in unanticipated ways,” they write.