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Chemical targeting of G-quadruplexes in telomeres and beyond for molecular cancer therapeutics

Abstract

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.

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Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (20K21555 and 20H04789 to HS), grants from the Translational Research Program; Strategic Promotion for Practical Application of Innovative Medical Technology (20lm0203003j0004 to HS and KN) and Project for Cancer Research and Therapeutic Evolution (21cm0106184h0001 to HS and KN), Japan Agency for Medical Research and Development, and funding from Nippon Foundation to HS. We thank Joe Barber Jr., PhD, from Edanz (https://www.jp.edanz.com/ac) for editing a draft of this paper.

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HS wrote the manuscript in consultation with KN and KS. All authors contributed to the final version of the manuscript.

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Correspondence to Hiroyuki Seimiya.

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HS received a research grant from the Nippon Foundation. KN and KS have no competing interests to declare.

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Seimiya, H., Nagasawa, K. & Shin-ya, K. Chemical targeting of G-quadruplexes in telomeres and beyond for molecular cancer therapeutics. J Antibiot 74, 617–628 (2021). https://doi.org/10.1038/s41429-021-00454-x

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