Degradation of G-Quadruplex Binding Proteins in Chromatin Using G4-Ligand-Based PROTACs

Abstract

Targeted protein degradation can intervene with the function of disease-related proteins. We present a conceptually novel approach to degrade proteins associated with DNA G-quadruplex (G4) secondary structures in a chromatin context. G4s form in open chromatin at transcriptionally active genes and are abundant in cancer states. Our bifunctional molecules are PROTACs that bind naturally occurring G4s, recruit E3 ubiquitin ligases and degrade G4-specific transcription factors and chromatin remodelers such as FUS, SMARCA4, and ATRX. These proteins are important therapeutic targets that play crucial roles in transcription regulation and DNA repair. Our approach has the potential to be exploited in a therapeutic strategy to target diseases characterized by aberrant G4 activity, such as cancers.