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.

PROTAC-Mediated HDAC7 Protein Degradation Unveils Its Deacetylase-Independent Proinflammatory Function in Macrophages.

Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan-inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC-based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)-stimulated macrophages and a mouse model.

A practical "preTACs-cytoblot" platform accelerates the streamlined development of PROTAC-based protein degraders.

With the growing importance of PROTAC-mediated protein degradation in drug discovery, robust synthetic methodologies and rapid screening assays are urgently needed. By harnessing the improved alkene hydroazidation reaction, we developed a novel strategy to introduce azido groups into the linker-E3 ligand conjugates and effectively created a range of prepacked terminal azide-labeled "preTACs" as PROTAC toolkit building blocks. Moreover, we demonstrated that preTACs are ready to conjugate to ligands targeting a protein of interest to generate libraries of chimeric degraders, which are subsequently screened for effective protein degradation directly from cultured cells with a cytoblot assay.