New technologies for chemical genetics

Chemical genetics, in which small molecules are used in lieu of mutations to study biological processes, requires large and diverse chemical libraries to specifically perturb different biological pathways. Here we describe a suite of technologies that enable chemical libraries prepared by split-pool solid phase synthesis to be screened in a diverse range of chemical genetic assays. Compounds are synthesized on 500 micron high-capacity polystyrene beads, and arrayed into individual wells of 384-well plates using a hand-held bead arrayer. Compounds are cleaved from synthesis beads using a chemically-resistant ceramic dispensing system, producing individual stock solutions of single compounds. Nanoliter volumes of these solutions are then transferred into assay plates using an array of stainless steel pins mounted on a robotic arm. We have designed reusable 1536- and 6144-well assay plates made of silicone rubber that can be cast in the laboratory and filled by hand. This integrated technology platform enables hundreds of biological assays to be performed from the product of a single synthesis bead, enabling the results of different chemical genetic experiments to be directly compared.