This project will focus on the development of a powerful new approach for the discovery of bioactive small molecules via cell-based phenotypic screening. DNA-encoded one bead one compound libraries built on small beads will be complexed with cells and suspended in solution. A photolabile linker will be cleaved, exposing the cells briefly to a high local concentration of the compound on the bead to which they are attached. The cells will be engineered to report a phenotype of interest through the increase of a fluorescent signal. Beads carrying positive cells will be isolated by FACS and the encoding tags sequenced, revealing the structures of the hits. Since we will use libraries of molecules capable of linking to targets covalently, the identification of the target will be simplified greatly. This system will be used to discover novel new chemotherapy agents.
This project will use develop a powerful technology for the discovery of bioactive small molecules through phenotypic screening using DNA-encoded libraries of compounds carrying weakly reactive electrophiles. The combination of the availability of millions of potential irreversible protein ligands and the power of the novel screening platform that will be established will revolutionize this currently difficult screening process.