Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes

Abstract

G-quadruplexes, a family of tetraplex helical nucleic acid topologies, have emerged in recent years as novel targets, with untapped potential for anticancer research. Their potential stems from the fact that G-quadruplexes occur in functionally-important regions of the human genome, such as the telomere tandem sequences, several proto-oncogene promoters, other regulatory regions and sequences of DNA (e.g. rDNA), as well as in mRNAs encoding for proteins with roles in tumorigenesis. Modulation of G-quadruplexes, via interaction with high-affinity ligands, leads to their stabilization, with numerous observed anticancer effects. Despite the fact that only a few lead compounds for G-quadruplex modulation have progressed to clinical trials so far, recent advancements in the field now create conditions that foster further development of drug candidates. This review highlights biological processes through which G-quadruplexes can exert their anticancer effects and describes, via selected case studies, progress of the last few years on the development of efficient and drug-like G-quadruplex-targeted ligands, intended to harness the anticancer potential offered by G-quadruplexes. The review finally provides a critical discussion of perceived challenges and limitations that have previously hampered the progression of G-quadruplex-targeted lead compounds to clinical trials, concluding with an optimistic future outlook.

On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents

“…In the present review we have provided, without demanding completeness, a brief overlook on the potential of G4 ligands as therapeutic agents in cancer ( Table 1 ). In particular, we draw the readers’ attention to few examples that have been paradigmatic to depict how small molecule-mediated stabilization of G4 structures may represent an intriguing strategy that could be implemented in the fight of cancer [ 14 , 15 , 16 , 17 , 18 , 29 ].…”

“…The variety of small molecules evaluated for their G4 stabilizing properties is countless [ 34 ]. Most of them have been reported to exert a remarkable antiproliferative activity accompanied, in some cases, by evidence of pharmacodynamic activity, when used as single agents in several in vitro models of human cancers [ 2 , 12 , 14 , 15 , 16 , 17 , 18 , 29 , 57 , 63 ]. Moreover, synergistic pharmacological interactions have been also documented for some G4 ligands when combined to conventional anticancer therapies [ 12 , 14 ], both in vitro and in vivo.…”

“…Although G4 structures could appear as elusive entities and their biological role still requires to be elucidated in depth, the evidence that these structures (i) are stable and detectable in human genomic DNA [ 24 ]; (ii) can be detected in living cells by specific antibodies or fluorescent probes [ 25 ]; (iii) are prevalent in tumor than in normal tissues [ 26 , 27 ], alongside the evidence that some human genetic disorders are driven by defects in the unwinding activity of G4-associated enzymes [ 28 ], indicates that G4 may represent suitable druggable targets. Indeed, during the past two decades several efforts have been made in the search of small molecules able to recognize and bind to G4 structures [ 2 , 15 , 18 , 29 ]. These compounds broadly share defined structural features, including (1) a large aromatic core for π-π stacking interactions with the G-quartet; (2) one or more flexible side-chains on the aromatic core that allow introducing specific functional groups to favor the interaction with grooves, loops or individual bases of the G4 [ 30 , 31 , 32 ].…”

“…It has been also reported that compounds with reduced planarity (i.e., lacking the flat aromatic core) may be amenable of G4 targeting through the interaction with the grooves and/or the nucleic acid backbone [ 33 ]. To date, several small molecules belonging to distinct chemical families have been designed and characterized as G4 ligands [ 34 ] and a subset of them have been evaluated for their therapeutic potential in cancer [ 14 , 15 , 16 , 17 , 18 , 29 ].…”

Interaction of 9-Methoxyluminarine with Different G-Quadruplex Topologies: Fluorescence and Circular Dichroism Studies

“…Intensive studies have revealed the formation of G-quadruplexes in vivo [ 20 , 21 , 22 , 23 ] and have provided evidence of their role in several key cellular processes, including gene transcription, chromatin epigenetics and DNA recombination. On the other hand, the linkage of G-quadruplex forming sequences with cancer diseases contributed to the rapid development of research focused on finding ligands, which can induce, stabilize or disrupt the G4 structure [ 24 , 25 , 26 , 27 ]. Since 2013, there has been a database containing the ligands tested against G-quadruplexes [ 28 ].…”