Extended Data Fig. 9: Impact of linker length on the degradation activity and subcellular targeting of G4L-PROTACs.
a, Box plots of log2 fold change in abundance for significantly (FDR < 0.05) downregulated proteins localized to cytosol versus nucleoplasm across eight G4L-PROTACs (relative to a negative control). Box plots show median, IQR, and whiskers (1.5× IQR); n = 3 independent biological replicates per compound. b, Pie chart summarizing the sub-cellular localization of proteins significantly down-regulated across 8 G4L-PROTACs (FDR < 0.05). Overall enrichment observed for nucleoplasmic (29.64%) and cytosolic (18.25%) proteins, followed by vesicles, plasma membrane, and other compartments. c, Proteomic rank summary for known G4-binding proteins (FDR < 0.05) across G4L-PROTACs with linkers of 7-23 atoms. Bars represent individual biological replicates (n = 3 per compound). d, Gene set enrichment analysis (GSEA) of proteomic changes in G4L-PROTAC2-treated cells. Up-regulated proteins (left) are enriched for pathways related to DNA damage response and KRAS signalling, while down-regulated proteins (right) include factors involved in metabolism, mesenchymal transition, and interferon response. Normalized enrichment scores (NES) are shown for selected Hallmark gene sets. e, Percentage overlap between degraded proteins and a curated RNA G4-binding protein list. f, Schematic illustrating how linker length may influence productive proximity between the recruited E3 ligase and proximal G4-associated proteins.
