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

Abstract

Nucleic acid sequences able to adopt a G-quadruplex conformation are overrepresented within the human genome. This evidence strongly suggests that these genomic regions have been evolutionary selected to play a pivotal role in several aspects of cell biology. In the present review article, we provide an overview on the biological impact of targeting G-quadruplexes in cancer. A variety of small molecules showing good G-quadruplex stabilizing properties has been reported to exert an antitumor activity in several preclinical models of human cancers. Moreover, promiscuous binders and multiple targeting G-quadruplex ligands, cancer cell defense responses and synthetic lethal interactions of G-quadruplex targeting have been also highlighted. Overall, evidence gathered thus far indicates that targeting G-quadruplex may represent an innovative and fascinating therapeutic approach for cancer. The continued methodological improvements, the development of specific tools and a careful consideration of the experimental settings in living systems will be useful to deepen our knowledge of G-quadruplex biology in cancer, to better define their role as therapeutic targets and to help design and develop novel and reliable G-quadruplex-based anticancer strategies.

Keywords: Anticancer therapy; Cancer; Cell defense mechanisms; G-quadruplex; Gene Promoters; Synthetic Lethality; Telomeres.

Figure 1

Schematic representation of a G-quartet arrangement and of a G4 structure. Examples of intramolecular and intermolecular G4 structures have been also depicted [2]. M+: monovalent cation.

Figure 2

Schematic representation of the dual, sometimes interconnected (dashed arrow), path elicited by ligand-mediated stabilization of telomeric G4 (created with BioRender.com).

Figure 3

Schematic representation of G4 ligand-mediated synthetic lethality. In this context, the complementary treatment with a G4 ligand can be exploited to enhance killing of cancer cells characterized by specific genetic deficiency or upon pharmacological/chemical inhibition of the activity/expression of specific genes (created with BioRender.com).

Figure 4

The chemical structures of the two G4 ligands under clinical testing and the related clinical trials have been reported. Study identifiers and information have been retrieved from www.clinicaltrials.gov accessed on 15 April 2021. N.A.: Not available.