title: Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies.
abstract: Human telomeric DNA (hTelo), present at the ends of chromosomes to protect their integrity during cell division, comprises tandem repeats of the sequence d(TTAGGG) which is known to form a G-quadruplex secondary structure. This unique structural formation of DNA is distinct from the well-known helical structure that most genomic DNA is thought to adopt, and has recently gained prominence as a molecular target for new types of anticancer agents. In particular, compounds that can stabilize the intramolecular G-quadruplex formed within the human telomeric DNA sequence can inhibit the activity of the enzyme telomerase which is known to be upregulated in tumor cells and is a major contributor to their immortality. This provides the basis for the discovery and development of small molecules with the potential for selective toxicity toward tumor cells. This review summarizes the various families of small molecules reported in the literature that have telomeric quadruplex stabilizing properties, and assesses the potential for compounds of this type to be developed as novel anticancer therapies. A future perspective is also presented, emphasizing the need for researchers to adopt approaches that will allow the discovery of molecules with more drug-like properties in order to improve the chances of lead molecules reaching the clinic in the next decade.
authors.affiliation: Institute of Pharmaceutical Science, Britannia House, King's College London, London SE1 1DB, UK.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Islam
authors.affiliation: Institute of Pharmaceutical Science, Britannia House, King's College London, London SE1 1DB, UK.
authors.forename: Paul Jm
authors.initials: PJ
authors.lastname: Jackson
authors.affiliation: Institute of Pharmaceutical Science, Britannia House, King's College London, London SE1 1DB, UK.
authors.forename: Khondaker M
authors.initials: KM
authors.lastname: Rahman
authors.affiliation: Institute of Pharmaceutical Science, Britannia House, King's College London, London SE1 1DB, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009690:Nucleic Acid Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016615:Telomere / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries
keywords: DNA G-quadruplex; DNA/small-molecule interaction; G-quadruplex targeting; anticancer agent; antitumor agent; drug discovery; human telomeres; molecular modeling; rational drug design; telomerase