Project Summary DNA-encoded library (DEL) technology has revolutionized the discovery of protein- binding small molecules. However, traditional DELs, where every molecule is connected to an encoding DNA and the library is produced as an intractable mixture, have not been useful for functional and phenotypic screening. We have been involved in the development of one bead one compound (OBOC) DELs, which can be used for functional and cell-based screens since beads are separable and only a small percentage of the molecules on the beads are linked directly to a DNA encoding tag. To date, the very small number of papers that have described activity-based screens of OBOC DELs have required the use of highly sophisticated microfluidics technology. This project will develop a cell-based screening platform for OBOC DELs that will not require any specialized equipment. If successful, this will make this powerful approach to the discovery of bioactive molecules far more accessible to the chemical biology community.