G-quadruplex interacting small molecules and drugs: from bench toward bedside

Abstract

G-quadruplexes are non-Watson-Crick four-stranded nucleic acid structures. Recent evidence points toward their existence in vivo and their implication in various biological processes. Over the past two decades, small molecules have been developed to specifically and selectively target these structures in order to dissect mechanisms they have been linked to. This has led to the development of potential therapeutic agents, particularly for anti-carcinogenic activity. Here, we first present how major biological roles of G-quadruplexes have been uncovered by the use of specifically designed small molecule probes. We use this to highlight how fundamental research has contributed to identifying biological functions of G-quadruplexes and their potential as therapeutic targets. We then discuss the development of G-quadruplex interacting small molecules as potential drug candidates.

Keywords::

• chromatin
• DNA damage
• G-quadruplex
• nucleic acids
• small molecule
• telomere
• therapeutics

Acknowledgements

The authors would like to thank RC Rancourt for critical reading of the manuscript; G Almouzni and her team for fruitful discussions and S Balasubramanian and his group for providing a stimulating research programme around G-quadruplex nucleic acids. The authors also thank Marie Curie/Nucleosome 4D and La Fondation pour la recherche médicale for postdoc fellowships (S.M.).

Financial & competing interests disclosure

R Rodriguez is funded by the Centre National de la Recherche Scientifique. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Recent evidence points toward the existence of G-quadruplexes in vivo.

• Small molecules have helped uncover biological functions of G-quadruplexes in cells.

• Major cellular responses to G-quadruplex interacting small molecules include: telomere uncapping and DNA damage response; genome-wide targeting of G-quadruplex hotspots leading to a DNA damage response and targeting promoter G-quadruplexes and or mRNA G-quadruplexes to influence transcription and/or translation.

• Targeting one type of G-quadruplex is challenging, given the existence of 350,000 putative G-quadruplex forming sequences throughout the human genome.

• Quarfloxin is the only G-quadruplex interacting small molecule that has completed Phase II clinical trials.

• Many promising G-quadruplex interacting small molecules could potentially be developed for clinical use, given very interesting growth inhibitory properties in cell culture and various xenografts.