Identification and validation of WDR5 WIN-site ligands via DNA-encoded chemical library screening

WD repeat-containing protein 5 (WDR5) is a scaffolding protein involved in critical protein-protein interactions and a promising target for therapeutic development. Novel small-molecule ligands targeting WDR5 were identified using the DELopen platform, a free-access DNA-encoded chemical library (DEL) for academic research. Through off-DNA structure-activity relationship studies and photoaffinity labeling, two promising initial leads, DBL-6-13 and DBL-6-33, were identified as new binders of WDR5. These compounds exhibited moderate to good binding affinities and were confirmed to bind the WIN-site through co-crystal structure analysis. Our findings demonstrate the utility of DEL technology in identifying ligands for challenging targets like WDR5, particularly within an academic research setting using the DELopen platform. The identified WDR5 ligands offer a foundation for further optimization and exploration as chemical probes for WDR5 research.