G-quadruplexes (G4s) are higher-order structures formed by guanine-rich 
sequences of nucleic acids, such as the telomeric 5'-TTAGGG-3'/5'-UUAGGG-3' 
repeats and those in gene regulatory regions. G4s regulate various biological 
events, including replication, transcription, and translation. Imbalanced G4 
dynamics is associated with diseases, such as cancer and neurodegenerative 
diseases. Telomestatin is a natural macrocyclic compound derived from 
Streptomyces anulatus 3533-SV4. It interacts with the guanine quartet via π-π 
stacking and potently stabilizes G4. Because G4 stabilization at the telomeric 
repeat inhibits the telomere-synthesizing enzyme telomerase, telomestatin was 
originally identified as a telomerase inhibitor. Whereas non-toxic doses of 
telomestatin induce gradual shortening of telomeres and eventual crisis in human 
cancer cells, higher doses trigger prompt replication stress and DNA damage 
responses, resulting in acute cell death. Suppression of the transcription and 
translation of G4-containing genes is also implicated in the anticancer effects 
of telomestatin. Because telomestatin is rare, labile, and insoluble, synthetic 
oxazole telomestatin derivatives have been developed and verified for their 
therapeutic efficacies in preclinical cancer models. Furthermore, a variety of 
G4-stabilizing compounds have been reported as promising seeds for molecular 
cancer therapeutics. To improve the design of future clinical studies, it will 
be important to identify predictive biomarkers of drug efficacy.