Targeted Degradation of G-Quadruplex Binding Cellular Proteins Using G4-Ligand-Based PROTACs

Targeted protein degradation is a cutting-edge approach in drug discovery, especially for addressing disease-related proteins that have been difficult to target with traditional methods. Here, we present a conceptually distinct strategy utilizing G-quadruplex (G4) ligand-based PROTACs (G4L-PROTACs) to selectively degrade proteins associated with DNA and RNA G-quadruplexes. Our method leverages G4 ligands that bind endogenous G4s and recruit E3 ubiquitin ligases to promote the degradation of cellular G4-binding proteins. We demonstrate degradation of a range of G4-specific binding proteins, including transcription factors and chromatin remodelers such as FUS, SMARCA4, and ATRX. These proteins play crucial roles in diverse cellular processes like transcription regulation and DNA repair, making them important therapeutic targets. Our results highlight the potential of G4L-PROTACs as a versatile tool for selectively degrading G4-binding proteins, offering new possibilities for therapeutic protein degraders, especially in diseases characterized by aberrant G4 activity, such as cancer.