G4-Ligand-Directed PROTACs Unveil DR1 as a Novel Ligand-Co-Binding G4-Protein and Reshape G4-Dependent Transcription.

G-quadruplexes (G4s) are dynamic nucleic acid structures whose biological impact is largely mediated by G4-binding proteins (G4BPs). While numerous G4BPs have been catalogued, the subset that specifically co-bind G4s in the presence of small-molecule ligands remains unexplored, limiting our understanding of ligand pharmacology. Here, we introduce G4-Ligand-Directed PROTACs (G4L-TACs), a chemical biology platform that couples high-affinity G4 ligands with E3 ubiquitin ligase recruiters to selectively degrade ligand-co-binding G4BPs. Using PDS-derived G4L-TACs, we identified the transcription factor DR1 as a previously unrecognized G4BP recruited to ligand-stabilized promoter G4s. G4L-TAC-mediated DR1 degradation relieved transcriptional repression at G4-rich oncogenic promoters, providing mechanistic insights into how G4 ligands influence gene expression beyond simple nucleic acid stabilization. These results establish G4L-TACs as a novel platform to discover ligand-co-binding G4BPs and reveal DR1 as a new regulatory node in G4-dependent transcription, offering a versatile tool for mechanistic dissection and therapeutic exploration.