Recent Advances in Anticancer Drugs Development: G-Quadruplex as New Drug Target

Abstract

JP, an open access journal Nucleic Acids are large biomolecules and indispensable for life. They include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic acids can adopt distinct non-canonical, highly compact secondary structure, G-quadruplex, in the dynamic region of chromosomal DNA and RNA transcripts, predominantly in telomeric sequences, and in promoter region of numerous genes including oncogenes such as Bcl-2 [1,2], VEGF [3,4], c-myc [5]. There are 376,000 putative quadruplex sequences (PQS) in the human genome that have been identified through genome-wide surveys based on a quadruplex folding rule [6], however, all of them may not exist in vivo. Recently, the existence of DNA G-quadruplex has been visualized on chromosomes in human cells [7]. These G-quadruplexes are an active target of drug discovery. The DNA G-quadruplexes formed in the promoter region of oncogene have been shown to be potential targets for anticancer drugs [8,9] and proteins. The formation of these quadruplexes in telomeres has been shown to regulate the activity of the enzyme telomerase, which maintains the length of telomeres and is involved in ~85% of all cancers. For example, Telomestatin [10,11], S2T1-6OTD (telomestatin synthetic Derivative) [12], SYUIQ-5 [13] interact with G-quadruplex formed in telomere and myc sequences and show their inhibitory activity in cancer cell growth. This has become a progressively large field of research. The G-quadruplexes are very condensed structures and formed by the ganosine (G)-rich DNA and RNA sequences and consists of several stacked G-tetrads. Each G-tetrad has four guanine arranged in a square planar arrangement and held together by hoogsteen hydrogen bonding. Besides this, each G-quadruplex structure is further stabilized by the presence of a monovalent cation, mainly potassium, which is localized in the center between each pair of tetrads. The G-quadruplexes could affect gene activity either by upregulation or down regulation, which can be achieved by inducing or stabilizing G-quadruplex formation through a G-quadruplex interacting molecule (small molecule drugs or protein) that can stabilize the G-quadruplex structure and thus perform their desired function [8]. The validation of drug-targeted G-quadruplex DNA and the modulation of cancer genes' expression has been intensely increased in the recent past, thus opening new avenue for cancer research.