telomestatin

Telomestatin is a natural macrocyclic small molecule, originally isolated from the bacterium *Streptomyces anulatus*, that acts as a potent and selective stabilizer of G-quadruplex (G4) DNA structures. It specifically binds to and stabilizes the G-quadruplex formed at telomeric DNA repeats, which physically blocks the enzyme telomerase from accessing the telomere and extending it. This stabilization also leads to the displacement of the shelterin protein complex—including proteins such as Protection of telomeres protein 1 (POT1) and Telomeric repeat-binding factor 2 (TRF2)—that protects telomeres from being recognized as DNA double-strand breaks. Consequently, telomestatin induces telomere dysfunction, chromosomal end-to-end fusions, and rapid apoptosis in cancer cells while showing relatively low toxicity to normal cells. Although telomestatin itself has faced challenges in clinical development due to its poor solubility and difficult total synthesis, it has served as a foundational lead compound for the development of synthetic analogs by institutions such as Institut Curie.