PhenoDEL: A Novel Screening Strategy Based on Intracellular Protein Degradation Activity
Yuichi Onda, Yurika Ochi, Toshihiro Araki, Miho Kageoka-Takahashi, Shuzo Takeda, Kazunori Yamada, Takehiko Ueda, Ken Ohno, Minoru Tanaka, Daiki Sakai, Miki Hasegawa, Yoshihito TanakaAbstract
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.