Thienopyrimidines as Novel Modulators of G Quadruplex Structures: Emerging Opportunities in Genome Targeted Therapy

G-quadruplexes (G4s) are higher-order nucleic acid structures that play key roles in transcription, replication, and genome stability. Their enrichment in oncogene promoters, telomeres, and viral genomes makes them attractive but underexploited drug targets. Over the past two decades, several chemical scaffolds have been designed to stabilize or remodel G4s, leading to proof-of-concept drug candidates such as quarfloxin and CX-5461. However, most of these ligands suffer from poor selectivity and unfavourable drug-like properties. Thienopyrimidines, a privileged heteroaromatic scaffold with structural similarity to purines, offer a promising alternative. Their compact, planar core allows efficient π-π stacking with G-quartets, while heteroatoms and tunable substituents enable selective groove and loop interactions. Emerging studies on thienopyrimidine derivatives already demonstrate DNA binding, cytotoxicity, and potential to stabilize oncogenic G4s. By integrating structure-activity insights from established ligands with the unique chemical versatility of thienopyrimidines, new generations of G4 modulators can be rationally designed for applications in oncology, infectious diseases, and genome-targeted therapeutics. This review highlights the structural rationale, preliminary evidence, and future opportunities for developing thienopyrimidines as selective G-quadruplex modulators.