Discovering Cell-Targeting Ligands and Cell-Surface Receptors by Selection of DNA-Encoded Chemical Libraries against Cancer Cells without Predefined Targets.

Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live cells is an effective strategy for discovering cell-targeting ligands. The DNA-encoded chemical library (DEL or DECL) technology has emerged as a robust tool in drug discovery and has been successfully utilized in identifying ligands for biological targets.

Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries.

DNA-encoded chemical libraries (DELs) have become a powerful technology platform in drug discovery. Dual-pharmacophore DELs display two sets of small molecules at the termini of DNA duplexes, thereby enabling the identification of synergistic binders against biological targets, and have been successfully applied in fragment-based ligand discovery and affinity maturation of known ligands. However, dual-pharmacophore DELs identify separate binders that require subsequent linking to obtain the full ligands, which is often challenging.

Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery.

Dynamic combinatorial libraries (DCLs) is a powerful tool for ligand discovery in biomedical research; however, the application of DCLs has been hampered by their low diversity. Recently, the concept of DNA encoding has been employed in DCLs to create DNA-encoded dynamic libraries (DEDLs); however, all current DEDLs are limited to fragment identification, and a challenging process of fragment linking is required after selection. We report an anchor-directed DEDL approach that can identify full ligand structures from large-scale DEDLs.