UC Irvine

High-throughput screening is the foundation for modern small molecule discovery, but DNA-encoded library (DEL) technology has emerged as an alternative approach to synthesizing and screening large collections for novel bioactive chemical matter. Currently, DEL screening is limited to affinity selection binding assays and, more recently, biochemical activity-based assays. This thesis describes the engineering of a cellular DEL activity assay that can serve as the basis for DEL screening on live cells. DEL beads were modified to support growth of cells and report on cellular activity using standard cellular reporter assays. Design of this platform took into account cell phototoxicity, cell viability and growth, and design of a model cellular signal transduction assay. This thesis successfully demonstrates proof-of-concept compatibility of the developed cellular assay with solid-phase DEL chemistry, paving the way for cellular phenotypic DEL screening technology.