In vitro proof-of-concept study demonstrates single-cell phenotypic screening of DNA-encoded libraries in reporter cells, indicating a scalable strategy for discovering targeted protein degraders.
Targeted protein degradation (TPD), including proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs), is a promising therapeutic approach. However, systematic discovery of such small molecules remains a major challenge. Here, we present PhenoDEL, a novel phenotypic DNA-encoded library (DEL) screening platform that integrates one-bead one-compound DEL (OBOC-DEL) with the Beacon optofluidic system for single-cell analysis. By coculturing individual OBOC-DEL beads and engineered reporter cells in nanoliter-scale chambers, PhenoDEL enables time-resolved, single-cell phenotypic evaluation and direct linkage between compound identity and intracellular response. As a proof-of-concept, we demonstrate discrimination of active and inactive on-bead compounds using an FKBP12F36V-EGFP degradation reporter in PC-3 cells, followed by DNA barcode decoding.
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Onda et al. (2026) studied this question.
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